Prodrugs of riluzole and their method of use

ABSTRACT

Pharmaceutical compositions of the invention include substituted riluzole prodrugs useful for the treatment of cancers including melanoma, breast cancer, brain cancer, and prostate cancer through the release of riluzole. Prodrugs of riluzole have enhanced stability to hepatic metabolism and are delivered into systemic circulation by oral administration, and then cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the filing date of U.S.Provisional Patent Application No. 61/612,210, filed Mar. 16, 2012, thedisclosure of which is incorporated by reference herein in its entirety.

STATEMENT OF FEDERALLY FUNDED RESEARCH

The U.S. Government has a paid-up license in this invention and theright in limited circumstances to require the patent owner to licenseothers on reasonable terms as provided for by the terms of grant numberR43 CA156781-01 awarded by the National Cancer Institute.

FIELD OF INVENTION

The present invention describes compounds and methods useful as prodrugagents, useful for the treatment of cancers including melanoma throughthe release of riluzole.

BACKGROUND OF THE INVENTION

A recently conducted Phase 0 human clinical trial of riluzole (Rilutek™)demonstrated dramatic efficacy in certain melanoma patients after only14 days of treatment. Riluzole, the only FDA approved drug to treatamyotrophic lateral sclerosis (ALS), showed clinical or radiologicevidence of tumor response in four of 12 patients with Stage III and IVmelanoma, cancer with a poor prognosis and severely limited treatmentoptions.

It is clear that the repositioned use of riluzole for melanoma or othercancers will be significantly constrained due to high levels ofvariability in hepatic metabolism of the drug as is the case for itsclinical use for ALS. We describe here prodrugs of riluzole in order toimprove the clinical efficacy of riluzole-based therapy, increasepatient compliance, and relieve human suffering. Metastatic melanoma hasfew treatment options, and the current therapeutic standard of care isdacarbazine which is a highly cytotoxic drug with severe side effectsincluding vomiting, headache and hair loss. Treatment with dacarbazinehas a median progression-free enhancement of survival time of only 1.5months. Riluzole (Rilutek™) is a generally non-toxic drug and currentlythe only FDA-approved treatment for amyotrophic lateral sclerosis (ALSor Lou Gehrig's disease).

We have recently shown that riluzole has dramatic anti-melanoma activityin vitro cellular assays, in mice and in a Phase 0 human clinical trial.In the clinic, four of twelve melanoma patients showed significantclinical or radiologic evidence of Stage III and IV tumor response.These results, along with the mild side-effect profile that riluzole hasshown among ALS patients, suggests that this drug has significantpotential for use as an improved treatment for metastatic melanoma.However, the therapeutic utility of riluzole itself in ALS andeventually for melanoma is very constrained by rapid first-passmetabolism in the liver and an exceptionally high level ofpatient-to-patient variability in the extent of the Cyp1A2-mediatedoxidative metabolism that is observed.

There is a long felt need for new treatments for melanoma that are bothdisease-modifying and effective in treating patients that are refractoryto current treatments. The present invention addresses the need toindentify new treatments for melanoma by identifying novel prodrugs ofriluzole which possess enhanced stability to hepatic metabolism and aredelivered into systemic circulation by oral administration. The riluzoleprodrugs are cleaved to release riluzole in the plasma via either anenzymatic or general biophysical release process.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed toward riluzole derivatives of formula(I),

including hydrates, solvates, pharmaceutically acceptable salts, andcomplexes thereof, wherein:

-   R¹ is selected from the group consisting of OR², CR^(3a)R^(3b)NH₂,    CR^(3a)R^(3b)NR^(7a)R^(7b), CH₂CH₂CO₂R⁴, CH₂CH₂CONHR⁵,    (CR^(6a)R^(6b))_(m)NR^(7a)R^(7b), CH₂Ar, and optionally substituted    phenyl ring;-   R² is selected from the group consisting of optionally substituted    C1-C6 alkyl and CH₂(CH₂)_(n)NR^(8a)R^(8b);-   n=1 or 2;

R^(3a) and R^(3b) are each independently selected from the groupconsisting of hydrogen, optionally substituted C1-C6 alkyl, optionallysubstituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl,CH₇R^(4a), optionally substituted phenyl, optionally substituted benzyl,optionally substituted CH₂CH₂Ar, optionally substituted CH₂heteroaryl,CH₂OR⁹, CH(CH₃)OR^(9a), CH₂SR⁹,CH₂CH₂SCH₃, CH₂CH₂SO₂CH₃,CH₂CH₂CH₂NR^(10a)R^(10b), CH₂COR^(9a), and CH₂CH₂COR^(9a);

-   R^(3a) and R^(3b) are taken together with the atom to which they are    bound to form an optionally substituted three to six membered    saturated heterocyclic ring comprising two to five carbon atoms and    a member selected from the group consisting of O, NR^(7a), S, and    SO₂;-   R⁴ is selected from the group consisting of hydrogen and optionally    substituted C1-C6 Alkyl;-   R^(4a) is selected from the group consisting of hydrogen, optionally    substituted C1-C6 Alkyl, optionally substituted C3-C6 cycloalkyl,    and optionally substituted four to six membered saturated    heterocyclic rings comprising three to five carbon atoms and a    member selected from the group consisting of O, NR^(7a), S, and SO₂;-   R⁵ is selected from the group consisting of hydrogen, optionally    substituted C1-C6 Alkyl, CH₂CH₂NR^(10a)R^(10b), and CH₂R¹¹;-   R^(6a) and R^(6b) are, at each occurrence, independently selected    from the group consisting of hydrogen and optionally substituted    C1-C6 alkyl;-   R^(6a) and R^(6b) are taken together with the atom to which they are    bound to form an optionally substituted 6 membered ring;-   m=3 or 4;-   m=1 or 2;-   R^(7a) and R^(7b) are each independently selected from the group    consisting of hydrogen, methyl, COR¹², and CO2R¹²;-   R^(3a) and R^(7a) are taken together with the atoms to which they    are bound to form an optionally substituted three to six membered    ring consisting of all carbons and one nitrogen atom;-   R^(3a) and R^(7a) are taken together with the atoms to which they    are bound to form an optionally substituted    1,2,3,4-tetrahydro-isoquinoline ring system;-   R^(3a) and R^(7a) are taken together with the atoms to which they    are bound to form an optionally substituted 2,3-Dihydro-1H-isoindole    ring system;-   R^(3a) and R^(7a) are taken together with the atoms to which they    are bound to form a optionally substituted six membered saturated    heterocyclic ring comprising four carbons, one nitrogen atom, and a    member selected from the group consisting of O, NR^(7a), S, and SO₂;-   R^(6a) and R^(7a) are taken together with the atoms to which they    are bound to form an optionally substituted three to six membered    ring consisting of all carbons and one nitrogen atom;-   R^(6a) and R^(7a) are taken together with the atoms to which they    are bound to form an optionally substituted    1,2,3,4-tetrahydro-isoquinoline ring system;-   R^(6a) and R^(7a) are taken together with the atoms to which they    are bound to form an optionally substituted 2,3-Dihydro-1H-isoindole    ring system;-   R^(6a) and R^(7a) are taken together with the atoms to which they    are bound to form a optionally substituted six membered saturated    heterocyclic ring consisting of four carbons, one nitrogen atom, and    a member from the group including O, NR^(7a), S, and SO₂;-   R^(8a) and R^(8b) are each independently optionally substituted    C1-C6 alkyl;-   R⁹ is selected from the group consisting of hydrogen, C1-C6 alkyl,    optionally substituted phenyl, optionally substituted benzyl, and    optionally substituted CH₂CH₂Ar;-   R^(9a) is selected from the group consisting of OH, C1-C6 alkoxy,    and NH₂.-   R^(10a) and R^(10b) are each independently is selected from the    group consisting of hydrogen and optionally substituted C1-C6 alkyl;-   R^(10a) and R^(10B) and are taken together with the atom to which    they are bound to form an optionally substituted ring having 5 to 6    ring atoms;-   R^(10a) and R^(10B) and are taken together with the atom to which    they are bound to form an optionally substituted ring having 5 to 6    ring atoms containing an oxygen;-   R^(10a) and R^(10B) and are taken together with the atom to which    they are bound to form an optionally substituted ring having 5 to 6    ring atoms containing two nitrogen atoms;-   R¹¹ is selected from the group consisting of optionally substituted    phenyl and optionally substituted heteroaryl;-   R¹² is C1-C6 alkyl.-   Ar is selected from the group consisting of optionally substituted    phenyl and optionally substituted naphthyl ring;-   Ar is optionally substituted with 0-5 moieties selected from the    group consisting of deuterium, halogen, trifluoromethyl,    triflouromethoxy, cyano, NR^(7a)R^(7b), CONR^(8a)R^(8b), C1-C6    alkyl, and C1-C6 alkoxy;

The compounds of the present invention include compounds having formula(II):

including hydrates, solvates, pharmaceutically acceptable salts, andcomplexes thereof, wherein:

-   R^(12a), R^(12b), R^(12c), R^(12d), and R^(12e) are each    independently selected from the group consisting of hydrogen,    deuterium, halogen, trifluoromethyl, triflouromethoxy, optionally    substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy;

The compounds of the present invention include compounds having formula(III):

including hydrates, solvates, pharmaceutically acceptable salts, andcomplexes thereof, wherein:

-   R^(12a), R^(12b), R^(12c), R^(12d), and R^(12e) are each    independently selected from the group consisting of hydrogen,    deuterium, halogen, trifluoromethyl, triflouromethoxy, optionally    substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy;

The compounds of the present invention include compounds having formula(Ia):

including hydrates, solvates, pharmaceutically acceptable salts, andcomplexes thereof, wherein:

-   R^(3a) and R^(3b) are each independently selected from the group    consisting of hydrogen, optionally substituted C1-C6 alkyl,    optionally substituted benzyl, optionally substituted CH₂CH₂Ar,    optionally substituted CH₂heteroaryl, CH₂OR⁹,    CH(CH₃)OR^(9,)CH₂SR⁹,CH₂CH₂SCH₃, CH₂CH₂CH₂NR^(10a)R^(10b),    CH₂COR^(9a), and CH₂CH₂COR^(9a);-   R^(11a) is selected from group consisting of optionally substituted    C1-C6 alkyl, COR⁴, and CO₂R⁴;-   R^(11a) and R^(3a) are taken together with the atoms to which they    are bound to form a 5 membered ring.-   R^(11a) and R^(3b) are taken together with the atoms to which they    are bound to form a 5 membered ring.

The compounds of the present invention include compounds having formula(IIa):

including hydrates, solvates, pharmaceutically acceptable salts, andcomplexes thereof.

The compounds of the present invention include compounds having formula(IIIa):

including hydrates, solvates, pharmaceutically acceptable salts, andcomplexes thereof.

The compounds of the present invention include compounds having formula(IVa):

including hydrates, solvates, pharmaceutically acceptable salts, andcomplexes thereof.

The compounds of the present invention include compounds having formula(Va):

including hydrates, solvates, pharmaceutically acceptable salts, andcomplexes thereof.

The present invention further relates to compositions comprising: aneffective amount of one or more compounds according to the presentinvention and an excipient.

The present invention yet further relates to an effective amount of oneor more compounds according to the present invention and an anticanceragent.

The present invention yet further relates to an effective amount of oneor more compounds according to the present invention and an anticanceragent and an excipient.

The present invention also relates to a method for treating orpreventing melanoma, said method comprising administering to a subjectan effective amount of a compound or composition according to thepresent invention.

The present invention yet further relates to a method for treating orpreventing melanoma, wherein said method comprises administering to asubject a composition comprising an effective amount of one or morecompounds according to the present invention and an excipient.

The present invention yet further relates to a method for treating orpreventing melanoma, wherein said method comprises administering to asubject a composition comprising an effective amount of one or morecompounds according to the present invention and an anticancer agent.

The present invention yet further relates to a method for treating orpreventing melanoma, wherein said method comprises administering to asubject a composition comprising an effective amount of one or morecompounds according to the present invention and an anticancer agent andan excipient.

The present invention also relates to a method for treating orpreventing disease or conditions associated with melanoma. Said methodscomprise administering to a subject an effective amount of a compound orcomposition according to the present invention.

The present invention yet further relates to a method for treating orpreventing disease or conditions associated with melanoma, wherein saidmethod comprises administering to a subject a composition comprising aneffective amount of one or more compounds according to the presentinvention and an excipient.

The present invention yet further relates to a method for treating orpreventing cancer, particularly melanoma.

The present invention yet further relates to a method for treating ofpreventing cancer, particularly ovarian cancer, cervical cancer, breastcancer, prostate cancer, testicular cancer, lung cancer, renal cancer,colorectal cancer, skin cancer, brain cancer, and leukemia, wherein saidmethod comprising administering to a subject an effective amount of acompound or composition according to the present invention.

The present invention yet further relates to a method for treating ofpreventing cancer, particularly ovarian cancer, cervical cancer, breastcancer, prostate cancer, testicular cancer, lung cancer, renal cancer,colorectal cancer, skin cancer, brain cancer, and leukemia, wherein saidmethod comprising administering to a subject an effective amount of acompound or composition according to the present invention and anexcipient.

The present invention yet further relates to a method for treating ofpreventing cancer, particularly ovarian cancer, cervical cancer, breastcancer, prostate cancer, testicular cancer, lung cancer, renal cancer,colorectal cancer, skin cancer, brain cancer, and leukemia, wherein saidmethod comprising administering to a subject an effective amount of acompound or composition according to the present invention and ananticancer agent.

The present invention yet further relates to a method for treating ofpreventing cancer, particularly ovarian cancer, cervical cancer, breastcancer, prostate cancer, testicular cancer, lung cancer, renal cancer,colorectal cancer, skin cancer, brain cancer, and leukemia, wherein saidmethod comprising administering to a subject an effective amount of acompound or composition according to the present invention and ananticancer agent and an excipient.

The present invention further relates to a process for preparing theriluzole prodrugs of the present invention.

These and other objects, features, and advantages will become apparentto those of ordinary skill in the art from a reading of the followingdetailed description and the appended claims. All percentages, ratiosand proportions herein are by weight, unless otherwise specified. Alltemperatures are in degrees Celsius (° C.) unless otherwise specified.All documents cited are in relevant part, incorporated herein byreference; the citation of any document is not to be construed as anadmission that it is prior art with respect to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The prodrugs of the present invention are capable of treating andpreventing melanoma by releasing riluzole in vivo. Prodrugs of riluzolehave enhanced stability to hepatic metabolism and are delivered intosystemic circulation by oral administration, and are then cleaved torelease riluzole in the plasma via either an enzymatic or generalbiophysical release process. Riluzole has dramatic anti-melanomaactivity in vitro, in mice and in a Phase 0 human clinical trial.

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes aredescribed as having, including, or comprising specific process steps, itis contemplated that compositions of the present teachings also consistessentially of, or consist of, the recited components, and that theprocesses of the present teachings also consist essentially of, orconsist of, the recited processing steps.

In the application, where an element or component is said to be includedin and/or selected from a list of recited elements or components, itshould be understood that the element or component can be any one of therecited elements or components and can be selected from the groupconsisting of two or more of the recited elements or components.

The use of the singular herein includes the plural (and vice versa)unless specifically stated otherwise. In addition, where the use of theterm “about” is before a quantitative value, the present teachings alsoinclude the specific quantitative value itself, unless specificallystated otherwise.

It should be understood that the order of steps or order for performingcertain actions is immaterial so long as the present teachings remainoperable. Moreover, two or more steps or actions can be conductedsimultaneously

As used herein, the term “halogen” shall mean chlorine, bromine,fluorine and iodine.

As used herein, unless otherwise noted, “alkyl” and “aliphatic” whetherused alone or as part of a substituent group refers to straight andbranched carbon chains having 1 to 20 carbon atoms or any number withinthis range, for example 1 to 6 carbon atoms or 1 to 4 carbon atoms.Designated numbers of carbon atoms (e.g. C₁₋₆) shall refer independentlyto the number of carbon atoms in an alkyl moiety or to the alkyl portionof a larger alkyl-containing substituent. Non-limiting examples of alkylgroups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, and the like. Alkyl groups can be optionallysubstituted. Non-limiting examples of substituted alkyl groups includehydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl,1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, 3-carboxypropyl, andthe like. In substituent groups with multiple alkyl groups such as(C₁₋₆alkyl)₂amino, the alkyl groups may be the same or different.

As used herein, “cycloalkyl,” whether used alone or as part of anothergroup, refers to a non-aromatic carbon-containing ring includingcyclized alkyl, alkenyl, and alkynyl groups, e.g., having from 3 to 14ring carbon atoms, preferably from 3 to 7 or 3 to 6 ring carbon atoms,or even 3 to 4 ring carbon atoms, and optionally containing one or more(e.g., 1, 2, or 3) double or triple bond. Cycloalkyl groups can bemonocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused,bridged, and/or spiro ring systems), wherein the carbon atoms arelocated inside or outside of the ring system. Any suitable ring positionof the cycloalkyl group can be covalently linked to the defined chemicalstructure. Cycloalkyl rings can be optionally substituted. Nonlimitingexamples of cycloalkyl groups include: cyclopropyl,2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl,2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl,decalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl,4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl,octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro3H inden 4 yl,decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, anddodecahydro-1H-fluorenyl. The term “cycloalkyl” also includescarbocyclic rings which are bicyclic hydrocarbon rings, non-limitingexamples of which include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1 ]heptanyl,1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo [2.2.2]octanyl, andbicyclo[3.3.3]undecanyl.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogen. Haloalkyl groupsinclude perhaloalkyl groups, wherein all hydrogens of an alkyl grouphave been replaced with halogens (e.g., —CF₃, CF₂CF₃). Haloalkyl groupscan optionally be substituted with one or more substituents in additionto halogen. Examples of haloalkyl groups include, but are not limitedto, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl,pentafluoroethyl, and pentachloroethyl groups.

The term “alkoxy” refers to the group —O-alkyl, wherein the alkyl groupis as defined above. Alkoxy groups optionally may be substituted. Theterm C₃-C₆ cyclic alkoxy refers to a ring containing 3 to 6 carbon atomsand at least one oxygen atom (e.g., tetrahydrofuran,tetrahydro-2H-pyran). C₃-C₆ cyclic alkoxy groups optionally may besubstituted.

The term “aryl,” wherein used alone or as part of another group, isdefined herein as an unsaturated, aromatic monocyclic ring of 6 carbonmembers or to an unsaturated, aromatic polycyclic ring of from 10 to 14carbon members. Aryl rings can be, for example, phenyl or naphthyl ringeach optionally substituted with one or more moieties capable ofreplacing one or more hydrogen atoms. Non-limiting examples of arylgroups include: phenyl, naphthylen-1-yl, naphthylen-2-yl,4-fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluorophenyl,2-(N,N-diethylamino)phenyl, 2-cyanophenyl, 2,6-di-tert-butylphenyl,3-methoxyphenyl, 8-hydroxynaphthylen-2-yl 4,5-dimethoxynaphthylen-1-yl,and 6-cyano-naphthylen-1-yl. Aryl groups also include, for example,phenyl or naphthyl rings fused with one or more saturated or partiallysaturated carbon rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl,indanyl), which can be substituted at one or more carbon atoms of thearomatic and/or saturated or partially saturated rings.

The term “arylalkyl” or “aralkyl” refers to the group -alkyl-aryl, wherethe alkyl and aryl groups are as defined herein. Aralkyl groups of thepresent invention are optionally substituted. Examples of arylalkylgroups include, for example, benzyl, 1-phenylethyl, 2-phenylethyl,3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl and the like.

The terms “heterocyclic” and/or “heterocycle” and/or “heterocylyl,”whether used alone or as part of another group, are defined herein asone or more ring having from 3 to 20 atoms wherein at least one atom inat least one ring is a heteroatom selected from nitrogen (N), oxygen(O), or sulfur (S), and wherein further the ring that includes theheteroatom is non-aromatic. In heterocycle groups that include 2 or morefused rings, the non-heteroatom bearing ring may be aryl (e.g.,indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocyclegroups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatomsindependently selected from nitrogen (N), oxygen (O), or sulfur (S). Oneor more N or S atoms in a heterocycle group can be oxidized. Heterocyclegroups can be optionally substituted.

Non-limiting examples of heterocyclic units having a single ringinclude: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl,imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl,isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl,hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl,piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl(valerolactam), 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole,and 1,2,3,4-tetrahydro-quinoline. Non-limiting examples of heterocyclicunits having 2 or more rings include: hexahydro-1H-pyrrolizinyl,3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl,3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl,chromanyl, isochromanyl, indolinyl, isoindolinyl, anddecahydro-1H-cycloocta[b]pyrrolyl.

The term “heteroaryl,” whether used alone or as part of another group,is defined herein as one or more rings having from 5 to 20 atoms whereinat least one atom in at least one ring is a heteroatom chosen fromnitrogen (N), oxygen (O), or sulfur (S), and wherein further at leastone of the rings that includes a heteroatom is aromatic. In heteroarylgroups that include 2 or more fused rings, the non-heteroatom bearingring may be a carbocycle (e.g., 6,7-Dihydro-SH-cyclopentapyrimidine) oraryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplaryheteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5ring heteroatoms independently selected from nitrogen (N), oxygen (O),or sulfur (S). One or more N or S atoms in a heteroaryl group can beoxidized. Heteroaryl groups can be substituted. Non-limiting examples ofheteroaryl rings containing a single ring include: 1,2,3,4-tetrazolyl,[1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl,oxazolyl, furanyl, thiopheneyl, pyrimidinyl, 2-phenylpyrimidinyl,pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limitingexamples of heteroaryl rings containing 2 or more fused rings include:benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl,9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl,7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl,benzo[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl,quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl,8-hydroxy-quinolinyl, and isoquinolinyl.

Unless otherwise noted, when two substituents are taken together to forma ring having a specified number of ring atoms (e.g., R² and R³ takentogether with the nitrogen (N) to which they are attached to form a ringhaving from 3 to 7 ring members), the ring can have carbon atoms andoptionally one or more (e.g., 1 to 3) additional heteroatomsindependently selected from nitrogen (N), oxygen (O), or sulfur (S). Thering can be saturated or partially saturated and can be optionallysubstituted.

For the purposed of the present invention fused ring units, as well asspirocyclic rings, bicyclic rings and the like, which comprise a singleheteroatom will be considered to belong to the cyclic familycorresponding to the heteroatom containing ring. For example,1,2,3,4-tetrahydroquinoline having the formula:

is, for the purposes of the present invention, considered a heterocyclicunit. 6,7-Dihydro-5H-cyclopentapyrimidine having the formula:

is, for the purposes of the present invention, considered a heteroarylunit. When a fused ring unit contains heteroatoms in both a saturatedand an aryl ring, the aryl ring will predominate and determine the typeof category to which the ring is assigned. For example,1,2,3,4-tetrahydro-[1,8]naphthyridine having the formula:

is, for the purposes of the present invention, considered a heteroarylunit.

Whenever a term or either of their prefix roots appear in a name of asubstituent the name is to be interpreted as including those limitationsprovided herein. For example, whenever the term “alkyl” or “aryl” oreither of their prefix roots appear in a name of a substituent (e.g.,arylalkyl, alkylamino) the name is to be interpreted as including thoselimitations given above for “alkyl” and “aryl.”

The term “substituted” is used throughout the specification. The term“substituted” is defined herein as a moiety, whether acyclic or cyclic,which has one or more hydrogen atoms replaced by a substituent orseveral (e.g., 1 to 10) substituents as defined herein below. Thesubstituents are capable of replacing one or two hydrogen atoms of asingle moiety at a time. In addition, these substituents can replace twohydrogen atoms on two adjacent carbons to form said substituent, newmoiety or unit. For example, a substituted unit that requires a singlehydrogen atom replacement includes halogen, hydroxyl, and the like. Atwo hydrogen atom replacement includes carbonyl, oximino, and the like.A two hydrogen atom replacement from adjacent carbon atoms includesepoxy, and the like. The term “substituted” is used throughout thepresent specification to indicate that a moiety can have one or more ofthe hydrogen atoms replaced by a substituent. When a moiety is describedas “substituted” any number of the hydrogen atoms may be replaced. Forexample, difluoromethyl is a substituted C₁ alkyl; trifluoromethyl is asubstituted C₁ alkyl; 4-hydroxyphenyl is a substituted aromatic ring;(N,N-dimethyl-5-amino)octanyl is a substituted C₈ alkyl;3-guanidinopropyl is a substituted C₃ alkyl; and 2-carboxypyridinyl is asubstituted heteroaryl.

The variable groups defined herein, e.g., alkyl, cycloalkyl, alkoxy,aryloxy, aryl, heterocycle and heteroaryl groups defined herein, whetherused alone or as part of another group, can be optionally substituted.Optionally substituted groups will be so indicated.

The following are non-limiting examples of substituents which cansubstitute for hydrogen atoms on a moiety: halogen (chlorine (Cl),bromine (Br), fluorine (F) and iodine(I)), —CN, —NO₂, oxo (═O), —OR¹³,—SR¹³, —N(R¹³)₂, —NR¹³C(O)R¹³, —SO₂R¹³, —SO₂OR¹³, —SO₂N(R¹³)₂, —C(O)R¹³,—C(O)OR¹³, —C(O)N(R¹³)₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₁₄ cycloalkyl, aryl, heterocycle, orheteroaryl, wherein each of the alkyl, haloalkyl, alkenyl, alkynyl,alkoxy, cycloalkyl, aryl, heterocycle, and heteroaryl groups isoptionally substituted with 1-10 (e.g., 1-6 or 1-4) groups selectedindependently from halogen, —CN, —NO₂, oxo, and R¹³; wherein R¹³, ateach occurrence, independently is hydrogen, —OR¹⁴, —SR¹⁴, —C(O)_(R) ¹⁴,—C(O)OR¹⁴, —C(O)N(R¹⁴)₂, —SO₂R¹⁴, —S(O)₂OR¹⁴, —N(R¹⁴)₂, —NR¹⁴C(O)R¹⁴,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, cycloalkyl(e.g., C₃₋₆ cycloalkyl), aryl, heterocycle, or heteroaryl, or two R¹³units taken together with the atom(s) to which they are bound form anoptionally substituted carbocycle or heterocycle wherein said carbocycleor heterocycle has 3 to 7 ring atoms; wherein R¹⁴, at each occurrence,independently is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, cycloalkyl (e.g., C₃₋₆ cycloalkyl), aryl, heterocycle, orheteroaryl, or two R¹⁴ units taken together with the atom(s) to whichthey are bound form an optionally substituted carbocycle or heterocyclewherein said carbocycle or heterocycle preferably has 3 to 7 ring atoms.

In some embodiments, the substituents are selected from

-   -   i) —OR¹⁵; for example, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃;    -   ii) —C(O)R¹⁵; for example, —COCH₃, —COCH₂CH₃, —COCH₂CH₂CH₃;    -   iii) —C(O)OR¹⁵; for example, —CO₂CH₃, —CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃;    -   iv) —C(O)N(R¹⁵)₂; for example, —CONH₂, —CONHCH₃, —CON(CH₃)₂;    -   v) —N(R¹⁵)₂; for example, —NH₂, —NHCH₃, —N(CH₃)₂, —NH(CH₇CH₃);    -   vi) halogen: —F, —Cl, —Br, and —I;    -   vii) —CH_(e)X_(g); wherein X is halogen, m is from 0 to 2,        e+g=3; for example, —CHF₂F, —CHF₃, —CF₃, —CCl₃, or —CBr₃;    -   viii) —SO₂R¹⁵; for example, —SO₂H; —SO₂CH₃; —SO₂C₆H₅;    -   ix) C₁-C₆ linear, branched, or cyclic alkyl;    -   x) Cyano    -   xi) Nitro;    -   xii) N(R¹⁵)C(O)R¹⁵;    -   xiii) Oxo (═O);    -   xiv) Heterocycle; and    -   xv) Heteroaryl.        wherein each R¹⁵ is independently hydrogen, optionally        substituted C₁-C₆ linear or branched alkyl (e.g., optionally        substituted C₁-C₄ linear or branched alkyl), or optionally        substituted C₃-C₆ cycloalkyl (e.g optionally substituted C₃-C₄        cycloalkyl); or two R¹⁵ units can be taken together to form a        ring comprising 3-7 ring atoms. In certain aspects, each R¹⁵ is        independently hydrogen, C₁-C₆ linear or branched alkyl        optionally substituted with halogen or C₃-C₆ cycloalkyl or C₃-C₆        cycloalkyl.

At various places in the present specification, substituents ofcompounds are disclosed in groups or in ranges. It is specificallyintended that the description include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆ alkyl” is specifically intended to individually discloseC₁, C₂, C₃, C₄, C₅, C₆, C₁-C₆, C₁-C₅, C₁-C₄, C₁-C₃, C₁-C₂, C₂-C₆, C₂-C₅,C₂-C₄, C₂-C₃, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₆, C₄-C₅, and C₅-C₆, alkyl.

For the purposes of the present invention the terms “compound,”“analog,” and “composition of matter” stand equally well for the prodrugagent described herein, including all enantiomeric forms, diastereomericforms, salts, and the like, and the terms “compound,” “analog,” and“composition of matter” are used interchangeably throughout the presentspecification.

Compounds described herein can contain an asymmetric atom (also referredas a chiral center), and some of the compounds can contain one or moreasymmetric atoms or centers, which can thus give rise to optical isomers(enantiomers) and diastereomers. The present teachings and compoundsdisclosed herein include such enantiomers and diastereomers, as well asthe racemic and resolved, enantiomerically pure R and S stereoisomers,as well as other mixtures of the R and S stereoisomers andpharmaceutically acceptable salts thereof. Optical isomers can beobtained in pure form by standard procedures known to those skilled inthe art, which include, but are not limited to, diastereomeric saltformation, kinetic resolution, and asymmetric synthesis. The presentteachings also encompass cis and trans isomers of compounds containingalkenyl moieties (e.g., alkenes and imines). It is also understood thatthe present teachings encompass all possible regioisomers, and mixturesthereof, which can be obtained in pure form by standard separationprocedures known to those skilled in the art, and include, but are notlimited to, column chromatography, thin-layer chromatography, andhigh-performance liquid chromatography.

Pharmaceutically acceptable salts of compounds of the present teachings,which can have an acidic moiety, can be formed using organic andinorganic bases. Both mono and polyanionic salts are contemplated,depending on the number of acidic hydrogens available for deprotonation.Suitable salts formed with bases include metal salts, such as alkalimetal or alkaline earth metal salts, for example sodium, potassium, ormagnesium salts; ammonia salts and organic amine salts, such as thoseformed with morpholine, thiomorpholine, piperidine, pyrrolidine, amono-, di- or tri-lower alkylamine (e.g., ethyl-tert-butyl-, diethyl-,diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-,di-, or trihydroxy lower alkylamine (e.g., mono-, di- ortriethanolamine). Specific non-limiting examples of inorganic basesinclude NaHCO₃, Na₂CO₃, KHCO₃, K₂CO₃, Cs₂CO₃, LiOH, NaOH, KOH, NaH₂PO₄,Na₂HPO₄, and Na₃PO₄. Internal salts also can be formed. Similarly, whena compound disclosed herein contains a basic moiety, salts can be formedusing organic and inorganic acids. For example, salts can be formed fromthe following acids: acetic, propionic, lactic, benzenesulfonic,benzoic, camphorsulfonic, citric, tartaric, succinic, dichloroacetic,ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic,mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic,pamoic, pantothenic, phosphoric, phthalic, propionic, succinic,sulfuric, tartaric, toluenesulfonic, and camphorsulfonic as well asother known pharmaceutically acceptable acids.

When any variable occurs more than one time in any constituent or in anyformula, its definition in each occurrence is independent of itsdefinition at every other occurrence (e.g., in N(R¹³)₂, each R¹³ may bethe same or different than the other). Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

The terms “treat” and “treating” and “treatment” as used herein, referto partially or completely alleviating, inhibiting, ameliorating and/orrelieving a condition from which a patient is suspected to suffer.

As used herein, “therapeutically effective” and “effective dose” referto a substance or an amount that elicits a desirable biological activityor effect.

As used herein, the term “riluzole prodrug” shall mean a compound thatare cleaved to release riluzole in the plasma via either an enzymatic orgeneral biophysical release process.

As used herein, the term “prodrug agent” shall mean a compound that arecleaved to release riluzole in the plasma via either an enzymatic orgeneral biophysical release process.

As used herein, the term “anticancer agent” shall mean a compound thatis useful for the treatment or prevention of cancer, including but notlimited to melanoma, ovarian cancer, cervical cancer, breast cancer,prostate cancer, testicular cancer, lung cancer, renal cancer,colorectal cancer, skin cancer, brain cancer, and leukemia

Except when noted, the terms “subject” or “patient” are usedinterchangeably and refer to mammals such as human patients andnon-human primates, as well as experimental animals such as rabbits,rats, and mice, and other animals. Accordingly, the term “subject” or“patient” as used herein means any mammalian patient or subject to whichthe compounds of the invention can be administered. In an exemplaryembodiment of the present invention, to identify subject patients fortreatment according to the methods of the invention, accepted screeningmethods are employed to determine risk factors associated with atargeted or suspected disease or condition or to determine the status ofan existing disease or condition in a subject. These screening methodsinclude, for example, conventional work-ups to deteimine risk factorsthat may be associated with the targeted or suspected disease orcondition. These and other routine methods allow the clinician to selectpatients in need of therapy using the methods and compounds of thepresent invention.

The Prodrug Agents:

The prodrug agents of the present invention are N-substituted riluzoleanalogs, and include all enantiomeric and diastereomeric forms andpharmaceutically accepted salts thereof having the formula (I):

including hydrates, solvates, pharmaceutically acceptable salts, andcomplexes thereof, wherein:

-   R¹ is selected from the group consisting of OR², CR^(3a)R^(3b)NH₂,    CR^(3a)R^(3b)NR^(7a)R^(7b), CH₂CH₂CO₂R⁴, CH₂CH₂CONHR⁵,    (CR^(6a)R^(6b))_(m)NR^(7a)R^(7b), CH₂Ar, and optionally substituted    phenyl ring; R² is selected from the group consisting of optionally    substituted C1-C6 alkyl and CH₂(CH₂)_(n)NR^(8a)R^(8b);-   n=1 or 2;

R^(3a) and R^(3b) are each independently selected from the groupconsisting of hydrogen, optionally substituted C1-C6 alkyl, optionallysubstituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl,CH₂R^(4a), optionally substituted phenyl, optionally substituted benzyl,optionally substituted CH₂CH₂Ar, optionally substituted CH₂heteroarylCH₂OR⁹, CH(CH₃)OR⁹, CH₂SR⁹, CH₂CH₂SCH₃, CH₂CH₂SO₂CH₃,CH₂CH₂CH₂NR^(10a)R^(10b), CH₂COR^(9a), and CH₂CH₂COR^(9a);

-   R^(3a) and R^(3b) are taken together with the atom to which they are    bound to form an optionally substituted three to six membered    saturated heterocyclic ring comprising two to five carbon atoms and    a member selected from the group consisting of O, NR^(7a), S, and    SO₂;-   R⁴ is selected from the group consisting of hydrogen and optionally    substituted C1-C6 alkyl;-   R^(4a) is selected from the group consisting of hydrogen,optionally    substituted C1-C6 Alkyl, optionally substituted C3-C6 cycloalkyl,    and optionally substituted four to six membered saturated    heterocyclic rings comprising three to five carbon atoms and a    member selected from the group consisting of O, NR^(7a), S, and SO₂;-   R⁵ is selected from the group consisting of hydrogen, optionally    substituted C1-C6 Alkyl, CH₂CH₂NR^(10a)R^(10b), and CH₂R¹¹;-   R^(6a) and R^(6b) are, at each occurrence, independently selected    from the group consisting of hydrogen and optionally substituted    C1-C6 alkyl;-   R^(6a) and R^(6b) are taken together with the atom to which they are    bound to form an optionally substituted 6 membered ring;-   m=3 or 4;-   m=1 or 2;-   R^(7a) and R^(7b) are each independently selected from the group    consisting of hydrogen methyl, COR¹², and CO₂R¹²;-   R^(3a) and R^(7a) are taken together with the atoms to which they    are bound to form an optionally substituted three to six membered    ring consisting of all carbons and one nitrogen atom;-   R^(3a) and R^(7a) are taken together with the atoms to which they    are bound to form an optionally substituted    1,2,3,4-tetrahydro-isoquinoline ring system;-   R^(3a) and R^(7a) are taken together with the atoms to which they    are bound to form an optionally substituted 2,3-Dihydro-1H-isoindole    ring system;-   R^(3a) and R^(7a) are taken together with the atoms to which they    are bound to form a optionally substituted six membered saturated    heterocyclic ring comprising four carbons, one nitrogen atom, and a    member selected from the group consisting of O, NR^(7a), S, and SO₂;-   R^(6a) and R^(7a) are taken together with the atoms to which they    are bound to form an optionally substituted three to six membered    ring consisting of all carbons and one nitrogen atom.-   R^(6a) and R^(7a) are taken together with the atoms to which they    are bound to form an optionally substituted    1,2,3,4-tetrahydro-isoquinoline ring system;-   R^(6a) and R^(7a) are taken together with the atoms to which they    are bound to form an optionally substituted 2,3-Dihydro-1H-isoindole    ring system;

R^(6a) and R^(7a) are taken together with the atoms to which they arebound to form a optionally substituted six membered saturatedheterocyclic ring comprising four carbons, one nitrogen atom, and amember selected from the group consisting of O, NR^(7a), S, and SO₂;

-   R^(8a) and R^(8b) are each independently optionally substituted    C1-C6 alkyl;-   R⁹ is selected from the group consisting of hydrogen, C1-C6 alkyl,    optionally substituted phenyl, optionally substituted benzyl, and    optionally substituted CH₂CH₂Ar;-   R⁹a is selected from the group consisting of OH, C1-C6 alkoxy, and    NH₂.-   R^(10a) and R^(10b) are each independently is selected from the    group consisting of hydrogen and optionally substituted C1-C6 alkyl;-   R^(10a) and R^(10B) and are taken together with the atom to which    they are bound to form an optionally substituted ring having 5 to 6    ring atoms;-   R^(10a) and R^(10B) and are taken together with the atom to which    they are bound to form an optionally substituted ring having 5 to 6    ring atoms containing an oxygen;-   R^(10a) and R^(10B) and are taken together with the atom to which    they are bound to form an optionally substituted ring having 5 to 6    ring atoms containing two nitrogen atoms;-   R¹¹ is selected from the group consisting of optionally substituted    phenyl and optionally substituted heteroaryl;-   R¹² is C1-C6 alkyl.-   Ar is selected from the group consisting of optionally substituted    phenyl and optionally substituted naphthyl ring;-   Ar is optionally substituted with 0-5 moieties selected from the    group consisting of deuterium, halogen, trifluoromethyl,    triflouromethoxy, cyano, NR^(7a)R^(7b), CONR^(8a)R^(8b), C1-C6    alkyl, and C1-C6 alkoxy;

The compounds of the present invention include compounds having formula(II):

including hydrates, solvates, pharmaceutically acceptable salts, andcomplexes thereof, wherein:

-   R^(12a), R^(12b), R^(12c), , R^(12d), and R^(12e) are each    independently selected from the group consisting of hydrogen,    deuterium, halogen, trifluoromethyl, triflouromethoxy, optionally    substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy;

The compounds of the present invention include compounds having formula(III):

including hydrates, solvates, pharmaceutically acceptable salts, andcomplexes thereof, wherein:

-   R^(12a), R^(12b), R^(12c), R^(12d), and R^(12e) are each    independently selected from the group consisting of hydrogen,    deuterium, halogen, trifluoromethyl, triflouromethoxy, optionally    substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy;

The compounds of the present invention include compounds having formula(Ia):

including hydrates, solvates, pharmaceutically acceptable salts, andcomplexes thereof, wherein:

-   R^(3a) and R^(3b) are each independently selected from the group    consisting of hydrogen, optionally substituted C1-C6 alkyl,    optionally substituted benzyl, optionally substituted CH₂CH₂Ar,    optionally substituted CH₂heteroaryl, and CH₂OR⁹;-   R^(11a) is selected from group consisting of optionally substituted    C1-C6 alkyl, COR⁴, and CO₂R⁴;-   R^(11a) and R^(3a) are taken together with the atoms to which they    are bound to form a 5 membered ring.-   R^(11a) and R^(3b) are taken together with the atoms to which they    are bound to form a 5 membered ring.

The compounds of the present invention include compounds having formula(IIa):

including hydrates, solvates, pharmaceutically acceptable salts, andcomplexes thereof.

The compounds of the present invention include compounds having formula(IIIa):

including hydrates, solvates, pharmaceutically acceptable salts, andcomplexes thereof.

The compounds of the present invention include compounds having formula(IVa):

including hydrates, solvates, pharmaceutically acceptable salts, andcomplexes thereof.

The compounds of the present invention include compounds having formula(Va):

including hydrates, solvates, pharmaceutically acceptable salts, andcomplexes thereof.

In some embodiments R¹ is OR².

In some embodiments R¹ is CR^(3a)R^(3b)NH₂.

In some embodiments R¹ is CR^(3a)R^(3b)NR^(7a)R^(7b).

In some embodiments R¹ is CH₂CH₂CO₂R⁴.

In some embodiments R¹ is CH₂CH₂CONHR⁵.

In some embodiments R¹ is (CR^(6a)R^(6b))^(m)NR^(7a)R^(7b)

In some embodiments R¹ is CH₂Ar.

In some embodiments R¹ is an optionally substituted phenyl ring.

In some embodiments R¹ is (CH₂)₄NHCH₃.

In some embodiments R¹ is (CH₂)₄NH₂.

In some embodiments R¹ is CH₂-2-nitrophenyl.

In some embodiments R¹ is 4-aminophenyl.

In some embodiments R¹ is

In some embodiments R² is optionally substituted C1-C6 alkyl.

In some embodiments R² is CH₂(CH₂)_(n)NR^(8a)R^(8b).

In some embodiments R² is CH₂CH₂NR^(8a)R^(8b).

In some embodiments R² is CH₂(CH₂)₂NR^(8a)R^(8b).

In some embodiments R² is CH₃.

In some embodiments R² is CH₂CH₃.

In some embodiments R² is (CH₂)₂CH₃

In some embodiments R² is (CH₂)₃CH₃

In some embodiments R² is CH₂CH(CH₃)₂

In some embodiments R² is (CH₂)₅CH₃

In some embodiments R² is (CH₂)₂N(CH₃)₂

In some embodiments R² is (CH₂)₃N(CH₃)₂

In some embodiments n is 1.

In some embodiments n is 2.

In some embodiments R^(3a) is hydrogen.

In some embodiments R^(3a) is optionally substituted C1-C6 alkyl.

In some embodiments R^(3a) is optionally substituted C1-C6 alkenyl.

In some embodiments R^(3a) is optionally substituted C1-C6 alkynyl.

In some embodiments R^(3a) is CH₂R^(4a).

In some embodiments R^(3a) is optionally substituted phenyl.

In some embodiments R^(3a) is optionally substituted benzyl.

In some embodiments R^(3a) is optionally substituted CH₂CH₂Ar.

In some embodiments R^(3a) is optionally substituted CH₂heteroaryl.

In some embodiments R^(3a) is CH₂OR⁹.

In some embodiments R^(3a) is CH(CH₃)OR⁹.

In some embodiments R^(3a) is CH₂SR⁹.

In some embodiments R^(3a) is CH₂CH₂SCH₃.

In some embodiments R^(3a) is CH₂CH₂SO₂CH_(3.)

In some embodiments R^(3a) is CH₂CH₂CH₂NR^(10a)R^(10b).

In some embodiments R^(3a) is CH₂COR^(9a).

In some embodiments R^(3a) is CH₂CH₂COR^(9a).

In some embodiments R^(3a) is CH₃.

In some embodiments R^(3a) is CH(CH₃)_(2.)

In some embodiments R^(3a) is CH₂Ph.

In some embodiments R^(3a) is CH₂OCH₂Ph.

In some embodiments R^(3a) is CH₂CH(CH₃)₂.

In some embodiments R^(3b) is hydrogen.

In some embodiments R^(3b) is optionally substituted C1-C6 alkyl.

In some embodiments R^(3b) is optionally substituted C1-C6 alkenyl.

In some embodiments R^(3b) is optionally substituted C1-C6 alkynyl.

In some embodiments R^(3b) is CH₂R^(4a).

In some embodiments R^(3b) is optionally substituted phenyl.

In some embodiments R^(3b) is optionally substituted benzyl.

In some embodiments R^(3b) is optionally substituted CH₂CH₂Ar.

In some embodiments R^(3b) is optionally substituted CH₂heteroaryl.

In some embodiments R^(3b) is CH₂OR⁹.

In some embodiments R^(3b) is CH(CH₃)OR⁹.

In some embodiments R^(3b) is CH₂SR⁹.

In some embodiments R^(3b) is CH₂CH₂SCH₃.

In some embodiments R^(3b) is CH₂CH₂SO₂CH_(3.)

In some embodiments R_(3b) is CH₂CH₂CH₂NR^(10a)R^(10b).

In some embodiments R^(3b) is CH₂COR^(9a).

In some embodiments R^(3b) is CH₂CH₂COR^(9a).

In some embodiments R^(3b) is CH₃.

In some embodiments R^(3b) is CH(CH₃)₂.

In some embodiments R^(3b) is CH₂Ph.

In some embodiments R^(3b) is CH₂OCH₂Ph.

In some embodiments R^(3b) is CH₂CH(CH₃)₂.

In some embodiments R^(3a) and R^(3b) are taken together with the atomto which they are bound to form an optionally substituted three to sixmembered saturated heterocyclic ring comprising two to five carbon atomsand a member selected from the group consisting of O, NR^(7a), S and,SO₂;

In some embodiments R⁴ is hydrogen.

In some embodiments R⁴ is optionally substituted C1-C6 alkyl.

In some embodiments R⁴ is CH_(3.)

In some embodiments R⁴ is C(CH₃)_(3.)

In some embodiments R^(4a) is hydrogen.

In some embodiments R^(4a) is optionally substituted C1-C6 alkyl.

In some embodiments R^(4a) is optionally substituted C3-C6 cycloalkyl.

In some embodiments R^(4a) is optionally substituted four to sixmembered saturated heterocyclic ring comprising three to five carbonatoms and a member selected from the group consisting of O, NR^(7a), S,and SO₂;

In some embodiments R⁵ is hydrogen.

In some embodiments R⁵ is optionally substituted C1-C6 Alkyl.

In some embodiments R⁵ is CH₂CH₂NR^(10a)R^(10b).

In some embodiments R⁵ is CH₂R¹¹.

In some embodiments R⁵ is CH₂-3-pyridyl.

In some embodiments R⁵ is

In some embodiments R^(6a) is hydrogen.

In some embodiments R^(6a) is optionally substituted C1-C6 alkyl.

In some embodiments R^(6b) is hydrogen.

In some embodiments R^(6b) is optionally substituted C1-C6 alkyl.

In some embodiments R^(6a) and R^(6b) are taken together with the atomto which they are bound to form an optionally substituted 6 memberedring.

In some embodiments in is 1.

In some embodiments m is 2.

In some embodiments m is 3.

In some embodiments m is 4.

In some embodiments R^(7a) is hydrogen.

In some embodiments R^(7a) is methyl.

In some embodiments R^(7a) is COR¹².

In some embodiments R^(7a) is CO2R¹².

In some embodiments R^(7b) is hydrogen.

In some embodiments R^(7b) is methyl.

In some embodiments R^(7b) is COR¹².

In some embodiments R^(7b) is CO2R¹².

In some embodiments R^(3a) and R^(7a) taken together can form a threemembered ring consisting of all carbons and one nitrogen atom.

In some embodiments R^(3a) and R^(7a) taken together can form a fourmembered ring consisting of all carbons and one nitrogen atom.

In some embodiments R^(3a) and R^(7a) taken together can form a fivemembered ring consisting of all carbons and one nitrogen atom.

In some embodiments R^(3a) and R^(7a) taken together can form a sixmembered ring consisting of all carbons and one nitrogen atom.

In some embodiments R^(3a) and R^(7a) are taken together with the atomsto which they are bound to form an optionally substituted1,2,3,4-tetrahydro-isoquinoline ring system.

In some embodiments R^(3a) and R^(7a) are taken together with the atomsto which they are bound to form an optionally substituted2,3-Dihydro-1H-isoindole ring system;

In some embodiments R^(3a) and R^(7a) are taken together with the atomsto which they are bound to form a optionally substituted six memberedsaturated heterocyclic ring comprising four carbons, one nitrogen atom,and a member selected from the group consisting of O, NR^(7a), S, andSO₂.

In some embodiments R^(6a) and R^(7a) taken together can form a threemembered ring consisting of all carbons and one nitrogen atom.

In some embodiments R^(6a) and R^(7a) taken together can form a fourmembered ring consisting of all carbons and one nitrogen atom.

In some embodiments R^(6a) and R^(7a) taken together can form a fivemembered ring consisting of all carbons and one nitrogen atom.

In some embodiments R^(6a) and R^(7a) taken together can form a sixmembered ring consisting of all carbons and one nitrogen atom.

In some embodiments R^(6a) and R^(7a) are taken together with the atomsto which they are bound to form an optionally substituted1,2,3,4-tetrahydro-isoquinoline ring system.

In some embodiments R^(6a) and R^(7a) are taken together with the atomsto which they are bound to form an optionally substituted2,3-Dihydro-1H-isoindole ring system;

In some embodiments R^(6a) and R^(7a) are taken together with the atomsto which they are bound to form a optionally substituted six memberedsaturated heterocyclic ring comprising four carbons, one nitrogen atom,and a member selected from the group consisting of O, NR^(7a), S, andSO₂.

In some embodiments R^(8a) is optionally substituted C1-C6 alkyl.

In some embodiments R^(8b) is optionally substituted C1-C6 alkyl.

In some embodiments R⁹ is hydrogen.

In some embodiments R⁹ is C1-C6 alkyl.

In some embodiments R⁹ is optionally substituted phenyl.

In some embodiments R⁹ is optionally substituted benzyl.

In some embodiments R⁹ is optionally substituted CH₂CH₂Ar.

In some embodiments R^(9a) is OH.

In some embodiments R^(9a) is C1-C6 alkoxy.

In some embodiments R^(9a) is NH₂.

In some embodiments R^(10a) is hydrogen.

In some embodiments R^(10a) is optionally substituted C1-C6 alkyl.

In some embodiments R^(10a) is hydrogen.

In some embodiments R^(10a) is optionally substituted C1-C6 alkyl.

In some embodiments R^(10a) and R^(10B) and are taken together with theatom to which they are bound to form an optionally substituted 5membered ring.

In some embodiments R^(10a) and R^(10B) and are taken together with theatom to which they are bound to form an optionally substituted 5membered ring containing an oxygen atom.

In some embodiments R^(10a) and R^(10B) and are taken together with theatom to which they are bound to form an optionally substituted 5membered ring containing two nitrogen atoms.

In some embodiments R^(10a) and R^(10B) and are taken together with theatom to which they are bound to form an optionally substituted 6membered ring.

In some embodiments R^(10a) and R^(10B) and are taken together with theatom to which they are bound to form an optionally substituted 6membered ring containing an oxygen atom.

In some embodiments R^(10a) and R^(10B) and are taken together with theatom to which they are bound to form an optionally substituted 6membered ring containing two nitrogen atoms.

In some embodiments R¹¹ is optionally substituted phenyl.

In some embodiments R¹¹ is optionally substituted heteroaryl.

In some embodiments R¹² is C1-C6 alkyl.

In some embodiments Ar is optionally substituted phenyl.

In some embodiments Ar is optionally substituted napthyl.

In some embodiments Ar is optionally substituted with 1, 2, 3, 4 or 5substituents independently selected from deuterium, halogen,trifluoromethyl, triflouromethoxy, cyano, NR^(7a)R^(7b),CONR^(8a)R^(8b), C1-C6 alkyl, and C1-C6 alkoxy.

In some embodiments R^(12a) is hydrogen.

In some embodiments R^(12a) is deuterium.

In some embodiments R^(12a) is optionally substituted C1-C6 alkyl.

In some embodiments R^(12a) is optionally substituted C1-C6 alkoxy.

In some embodiments R^(12a) is halogen.

In some embodiments R^(12a) is fluorine, chlorine, methyl, methoxy,trifluoromethyl, or triflouromethoxy.

In some embodiments R^(12b) is hydrogen.

In some embodiments R^(12b) is deuterium.

In some embodiments R^(12b) is optionally substituted C1-C6 alkyl.

In some embodiments R^(12b) is optionally substituted C1-C6 alkoxy.

In some embodiments R^(12b) is halogen.

In some embodiments R^(12b) is fluorine, chlorine, methyl, methoxy,trifluoromethyl, or triflouromethoxy.

In some embodiments R^(12c) is hydrogen.

In some embodiments R^(12c) is deuterium.

In some embodiments R^(12c) is optionally substituted C1-C6 alkyl.

In some embodiments R^(12c) is optionally substituted C1-C6 alkoxy.

In some embodiments R^(12c) is halogen.

In some embodiments R^(12c) is fluorine, chlorine, methyl, methoxy,trifluoromethyl, or triflouromethoxy.

In some embodiments R^(12d) is hydrogen.

In some embodiments R^(12d) is deuterium.

In some embodiments R^(12d) is optionally substituted C1-C6 alkyl.

In some embodiments R^(12d) is optionally substituted C1-C6 alkoxy.

In some embodiments R^(12d) is halogen.

In some embodiments R^(12d) is fluorine, chlorine, methyl, methoxy,trifluoromethyl, or triflouromethoxy.

In some embodiments R^(12e) is hydrogen.

In some embodiments R^(12e) is deuterium.

In some embodiments R^(12e) is optionally substituted C1-C6 alkyl.

In some embodiments R^(12e) is optionally substituted C1-C6 alkoxy.

In some embodiments R^(12e) is halogen.

In some embodiments R^(12e) is fluorine, chlorine, methyl, methoxy,trifluoromethyl, or triflouromethoxy.

In some embodiments R^(11a) is optionally substituted C1-C6 alkyl.

In some embodiments R^(11a) is COR⁴.

In some embodiments R^(11a) is CO₂R⁴.

In some embodiments R^(11a) and R^(3b) are taken together with the atomsto which they are bound to form a 5 membered ring.

In some embodiments R^(11a) and R^(3b) are taken together with the atomsto which they are bound to form a 5 membered ring.

Exemplary embodiments include compounds having the formula (I) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R¹ are defined herein below in Table 1.

TABLE 1 Entry R¹  1 (CH₂)₄NHCH₃  2 (CH₂)₄NH₂  3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15 CH₂-2-nitrophenyl 16 4-aminophenyl 17

18

19

20

21

22

21

22

23

24

25

26

Exemplary embodiments include compounds having the formula (IV) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R² are defined herein below in Table 2.

TABLE 2 Entry R² 1 CH₃ 2 CH₂CH₃ 3 (CH₂)₂CH₃ 4 (CH₂)₃CH₃ 5 CH₂CH(CH₃)₂ 6(CH₂)₄CH₃ 7 (CH₂)₅CH₃ 8 (CII₂)₂N(CII₃)₂ 9 (CH₂)₃N(CH₃)2

Exemplary embodiments include compounds having the formula (V) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R^(3a) and R^(3b) are defined hereinbelow in Table 3

TABLE 3 Entry R^(3a) R^(3b) 1 H H 2 H CH₃ 3 H CH(CH₃)₂ 4 H CH₂Ph 5 HCH₂OCH₂Ph 6 H CH₂CH(CH₃)₂ 7 CH₃ H 8 CH(CH₃)₂ H 9 CH₂Ph H 10 CH₂OCH₂Ph H11 CH₂CH(CH₃)₂ H 12 H CH₂OCH₃ 13 CH₂OCH₃ H 14 H CH₂OC(CH₃)₃ 15CH₂OC(CH₃)₃ H 16 CH(CH₃)CH₂CH₃ H 17 H CH(CH₃)CH₂CH₃ 18 CH₃ CH₃

Exemplary embodiments include compounds having the formula (VI) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R⁴ are defined herein below in Table 4.

TABLE 4 Entry R⁴ 1 H 2 CH₃ 3 C(CH₃)₃

Exemplary embodiments include compounds having the formula (VII) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R⁵ are defined herein below in Table 5.

TABLE 5 Entry R⁵ 1 CH₂-3-pyridyl 2

Exemplary embodiments include compounds having the formula (II) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R^(12a), R^(12b) R^(12c), R^(12d), andR^(12e) are defined herein below in Table 6.

TABLE 6 Entry R^(12a) R^(12b) R^(12c) R^(12d) R^(12e) 1 F H H H H 2 H FH H H 3 H H F H H 4 Cl H H H H 5 H Cl H H H 6 H H Cl H H 7 OCF₃ H H H H8 H OCF₃ H H H 9 H H OCF₃ H H 10 H H D H H 11 CH₃ H H H H 12 H CH₃ H H H13 H H CH₃ H H 14 CF₃ H H H H 15 H CF₃ H H H 16 H CF₃ H H 17 OCF₃ H H HH 18 H OCF₃ H H H 19 H OCF₃ H H 20 OCH₃ H H H H 21 H OCH₃ H H H 22 H HOCH₃ H H 23 F F H H H 24 H F F H H 25 F H F H H 26 Cl Cl H H H 27 Cl HCl H H 28 II Cl Cl II II 29 OCF₃ F H H H 30 D D D D D 31 CH₃ CH₃ H H H32 CF₃ F H H H 33 OCF₃ F H H H 34 OCH₃ F H H H

Exemplary embodiments include compounds having the formula (III) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R^(12a), R^(12b) R^(12c), R^(12d), andR^(12e) are defined herein below in Table 7.

TABLE 7 Entry R^(12a) R^(12b) R^(12c) R^(12d) R^(12e) 1 F H H H H 2 H FH H H 3 H H F H H 4 Cl H H H H 5 H Cl H H H 6 H H Cl H H 7 OCF₃ H H H H8 H OCF₃ H H H 9 H H OCF₃ H H 10 H H D H H 11 CH₃ H H H H 12 H CH₃ H H H13 H H CH₃ H H 14 CF₃ H H H H 15 II CF₃ II II II 16 H H CF₃ H H 17 OCH₃H H H H 18 H OCH₃ H H H 19 H H OCH₃ H H 20 F F H H H 21 F H F H H 22 H FF H H 23 Cl Cl H H H 24 Cl H Cl H H 25 H Cl Cl H H 26 OCF₃ F H H H 27 DD D D D 28 CH₃ CH₃ H H H 29 CF₃ F H H H 30 OCF₃ F H H H 31 OCH₃ F H H H

Exemplary embodiments include compounds having the formula (Ia) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R^(3a), R^(3b), and R^(11a) are definedherein below in Table 8.

TABLE 8 Entry R^(3a) R^(11a) R^(3b)  1 CH₂CO₂H H H  2 CH₂CONH₂ H H  3CH₂CH₂CO₂H H H  4 CH₂CH₂CONH₂ H H  5 CH₂CH₂SCH₃ H H  6 CH₂CH₂SO₂CH₃ H H 7 H H CH₂CO₂H  8 H H CH₂CONH₂  9 H H CH₂CH₂CO₂H 10 H H CH₂CH₂CONH₂ 11 HH CH₂CH₂SCH₃ 12 H H CH₂CH₂SO₂CH₃ 13

H H 14

H H 15

H H 16

H H 17

H H 18

H H 19 H H

20 H H

21 H H

22 H H

23 H H

24 H H

25 H COCH₃ H 26 H COCH₃ CH₃ 27 H COCH₃ CH(CH₃)₂ 28 H COCH₃ CH₂Ph 29 HCOCH₃ CH₂OCH₂Ph 30 H COCH₃ CH₂CH(CH₃)₂ 31 CH₃ COCH₃ H 32 CH(CH₃)₂ COCH₃H 33 CH₂Ph COCH₃ H 34 CH₂OCH₂Ph COCH₃ H 35 CH₂CH(CH₃)₂ COCH₃ H 36 HCO₂C(CH₃)₃ H 37 H CO₂C(CH₃)₃ CH₃ 38 H CO₂C(CH₃)₃ CH(CH₃)₂ 39 HCO₂C(CH₃)₃ CH₂Ph 40 H CO₂C(CH₃)₃ CH₂OCH₂Ph 41 H CO₂C(CH₃)₃ CH₂CH(CH₃)₂42 CH₃ CO₂C(CH₃)₃ H 43 CH(CH₃)₂ CO₂C(CH₃)₃ H 44 CH₂Ph CO₂C(CH₃)₃ H 45CH₂OCH₂Ph CO₂C(CH₃)₃ H 46 CH₂CH(CH₃)₂ CO₂C(CH₃)₃ H 47 —CH₂CH₂CH₂— H 48 H—CH₂CH₂CH₂—

Exemplary embodiments include compounds having the formula (I), (II),(III), (IV), (V), (VI), (VII), (Ia) or a pharmaceutically acceptablesalt form thereof, in combination with an anticancer agent. Exemplaryembodiments of anticancer agents include but are not limited toVemurafenib, Ipilimumab, Masitinib, Sorafenib, Lenalidomide, Oblimersen,Trametinib, Dabrafenib, RO5185426, Veliparib, Bosentan, YM155, CNTO 95,CR011-vcMMAE, CY503, Lenvatinib, Avastin, Tasidotin, Ramucirumab,IPI-504, Tasisulam, KW2871, MPC-6827, RAF265, Dovitinib, Everolimus,MEK162, BKM120, Nilotinib, Reolysin, 825A, Tremelimumab, PI-88,Elesclomol, STA9090, and Allovectin-7.

For the purposes of the present invention, a compound depicted by theracemic formula will stand equally well for either of the twoenantiomers or mixtures thereof, or in the case where a second chiralcenter is present, all diastereomers.

For the purposes of demonstrating the manner in which the compounds ofthe present invention are named and referred to herein, the compoundhaving the formula:

has the chemical name (6-trifluoromethoxy-benzothiazol-2-yl)-carbamicacid methyl ester.

For the purposes of demonstrating the manner in which the compounds ofthe present invention are named and referred to herein, the compoundhaving the formula:

has the chemical name (6-trifluoromethoxy-benzothiazol-2-yl)-carbamicacid methyl ester.

For the purposes of demonstrating the manner in which the compounds ofthe present invention are named and referred to herein, the compoundhaving the formula:

has the chemical name(S)-2-amino-3-methyl-N-(6-trifluoromethoxy-benzothiazol-2-yl)-butyramide.

For the purposes of the present invention, a compound depicted by theracemic formula, for example:

will stand equally well for either of the two enantiomers having theformula:

or the formula:

or mixtures thereof, or in the case where a second chiral center ispresent, all diastereomers.

In all of the embodiments provided herein, examples of suitable optionalsubstituents are not intended to limit the scope of the claimedinvention. The compounds of the invention may contain any of thesubstituents, or combinations of substituents, provided herein.

Process

Compounds of the present teachings can be prepared in accordance withthe procedures outlined herein, from commercially available startingmaterials, compounds known in the literature, or readily preparedintermediates, by employing standard synthetic methods and proceduresknown to those skilled in the art. Standard synthetic methods andprocedures for the preparation of organic molecules and functional grouptransformations and manipulations can be readily obtained from therelevant scientific literature or from standard textbooks in the field.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions can vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures. Those skilled in the art of organic synthesiswill recognize that the nature and order of the synthetic stepspresented can be varied for the purpose of optimizing the formation ofthe compounds described herein.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C), infrared spectroscopy, spectrophotometry(e.g., UV-visible), mass spectrometry, or by chromatography such as highpressure liquid chromatography (HPLC), gas chromatography (GC),gel-permeation chromatography (GPC), or thin layer chromatography (TLC).

Preparation of the compounds can involve protection and deprotection ofvarious chemical groups. The need for protection and deprotection andthe selection of appropriate protecting groups can be readily determinedby one skilled in the art. The chemistry of protecting groups can befound, for example, in Greene et al., Protective Groups in OrganicSynthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of whichis incorporated by reference herein for all purposes.

The reactions or the processes described herein can be carried out insuitable solvents which can be readily selected by one skilled in theart of organic synthesis. Suitable solvents typically are substantiallynonreactive with the reactants, intermediates, and/or products at thetemperatures at which the reactions are carried out, i.e., temperaturesthat can range from the solvent's freezing temperature to the solvent'sboiling temperature. A given reaction can be carried out in one solventor a mixture of more than one solvent. Depending on the particularreaction step, suitable solvents for a particular reaction step can beselected.

The compounds of these teachings can be prepared by methods known in theart of organic chemistry. The reagents used in the preparation of thecompounds of these teachings can be either commercially obtained or canbe prepared by standard procedures described in the literature. Forexample, compounds of the present invention can be prepared according tothe method illustrated in the General Synthetic Schemes:

General Synthetic Schemes for Preparation of Compounds.

The reagents used in the preparation of the compounds of this inventioncan be either commercially obtained or can be prepared by standardprocedures described in the literature. In accordance with thisinvention, compounds in the genus may be produced by one of thefollowing reaction schemes.

Compounds of formula (I) may be prepared according to the processoutlined in Scheme 1.

Riluzole, a known compound, is reacted with an electrophile such as anacid chloride, acid anhydride, a chloroformate, and the like, in asuitable solvent such as N,N-dimethylformamide, 1,4-dioxane,tetrahydrofuran, methylene chloride and the like in the presence of asuitable basesuch as triethylamine, diisopropylamine, orN-methylmorpholine and the like, to give compounds of formula (I)directly or a compound of the formula (IX). Alternatively, Riluzole isreacted with a carboxylic acid in the presence of an activating agentsuch as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, N,N′-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, and the like. in asuitable solvent such as N,N-dimethylformamide, 1,4-dioxane,tetrahydrofuran, methylene chloride and the like, optionally in thepresence of a suitable base such as triethylamine, diisopropylamine,N-methylmorpholine, pyridine, and the like, to give compounds of formula(I) directly or a compound of the formula (IX).

Compounds of the formula (IX) can be converted by compounds of theformula (I) by removal of the protecting group. The protecting group canbe remove by treatment under suitable conditions such as 1) with acid,such as hydrogen chloride, trifluoroacetic acid, and the like in organicsolvent such as 1,4-dioxane, dichloromethane, and the like, or 2)hydrogen in the presence of a catalyst such as palladium on activatedcarbon, platinum oxide and the like in an organic solvent such as ethylacetate, methanol, ethanol or 3) base such as litium hydroxide, sodiumhydroxide, potassium carbonate and the like in a solvent like water,methanol, tetrahydrofuran and the like to provide compounds of theformula (I).

Compounds of formula (Ia) may be prepared according to the processoutlined in Scheme 2.

Riluzole is reacted with a compound of the formula (IXa) wherein PG is asuitable protecting group in the presence of an activating agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, and the like. in a suitable solvent such asN,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chlorideand the like, optionally in the presence of a suitable base such astriethylamine, diisopropylamine, N-methylmorpholine, pyridine, and thelike, to give compounds of formula (IXb).

Compounds of the formula (IXb) can be converted by compounds of theformula (IXa) by removal of the protecting group. The protecting groupcan be remove by treatment under suitable conditions such as 1) withacid, such as hydrogen chloride, trifluoroacetic acid, and the like inorganic solvent such as 1,4-dioxane, dichloromethane, and the like, or2) hydrogen in the presence of a catalyst such as palladium on activatedcarbon, platinum oxide and the like in an organic solvent such as ethylacetate, methanol, ethanol or 3) base such as litium hydroxide, sodiumhydroxide, potassium carbonate and the like in a solvent like water,methanol, tetrahydrofuran and the like to provide compounds of theformula (IXa).

The Examples provided below provide representative methods for preparingexemplary compounds of the present invention. The skilled practitionerwill know how to substitute the appropriate reagents, starting materialsand purification methods known to those skilled in the art, in order toprepare the compounds of the present invention.

¹H-NMR spectra were obtained on a Varian Mercury 300-MHz NMR. Purity (%)and mass spectral data were determined with a Waters Alliance 2695HPLC/MS (Waters Symmetry C18, 4.6×75 mm, 3.5 μm) with a 2996 diode arraydetector from 210-400 nm.

EXAMPLES

Example 1 provides a method for preparing representative compound offormula (I). The skilled practitioner will know how to substitute theappropriate reagents, starting materials and purification methods knownto those skilled in the art, in order to prepare additional compounds ofthe present invention.

Example 1 2-Amino-N-(6-trifluoromethoxy-benzothiazol-2-yl)-acetamide,Cpd 1.

6-Trifluoromethoxy-benzothiazol-2-ylamine (100 mg, 0.42 mmol),tert-butoxycarbonylamino-acetic acid (75 mg, 0.43 mmol), and EDCI (123mg, 0.65 mmol) were combined in methylene chloride (5 mL) and strirred24 h at ambient temperature. The reaction was washed with 0.1N HC1 (2×10mL), diced over magnesium sulfate, filtered, and then concentrated.Chromatography on silica gel using 20% ethyl acetate: hexanes as eluentand then concentration afforded an oil. The oil was dissolved in 4N HC1and 1,4-dioxane and stirred 3 h. The reaction was concentrated to afford2-Amino-N-(6-trifluoromethoxy-benzothiazol-2-yl)-acetamide, Cpd 1. ¹HNMR (300 MHz, DMSO) δ 8.43 (s, 1H), 8.17 (s, 1H), 7.89 (t, J=10.4 Hz,1H), 7.56-6.99 (m, 2H), 3.98 (m, 2H). MS m/z (M⁺) 291.9.

Following the procedure described above for Example 1 and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compounds of thepresent invention (table 9) were prepared:

TABLE 9 Compound Compound Name and Characterization Data 2(R)-2-Amino-N-(6-trifluoromethoxy-benzothiazol-2-yl)- propionamide: ¹HNMR (300 MHz, DMSO) δ 8.57 (s, 1H), 8.18 (s, 1H), 7.88 (d, J = 8.8 Hz,1H), 7.46 (d, J = 8.8 Hz, 1H), 3.98 (bs, 3H), 1.46 (d, J = 7.1 Hz, 3H).MS m/z (M⁺) 305.9 4(R)-2-Amino-3-phenyl-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propionamide: ¹H NMR (300 MHz, DMSO) δ 8.75 (bs, 2H), 8.31 (s, 1H), 7.99(d, J = 8.9 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.42 (m, 4H), 4.53 (bs,1H), 3.44 (s, 2H), 3.32 (m, 2H). MS m/z (M⁺) 381.9 5(R)-2-Amino-3-benzyloxy-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propionamide: ¹H NMR (300 MHz, DMSO) δ 8.37 (d, J = 103.5 Hz, 1H), 8.20(s, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 9.6 Hz, 1H), 7.40-7.18(m, 5H), 4.57 (q, J = 12.4 Hz, 2H), 4.42 (m, 2H), 4.06-3.82 (m, 1H),3.50 (s, 1H). MS m/z. (M⁺) 411.9 7(S)-2-Amino-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propionamide: ¹HNMR (300 MHz, DMSO) δ 8.57 (s, 1H), 8.18 (s, 1H), 7.88 (d, J = 8.8 Hz,1H), 7.46 (d, J = 8.8 Hz, 1H), 4.78-3.63 (m, 1H), 1.46 (d, J = 7.1 Hz,3H). MS m/z (M⁺) 305.9 11(S)-2-Amino-3-methyl-N-(6-trifluoromethoxy-benzothiazol-2-yl)-butyramide ¹H NMR (300 MHz, DMSO) δ 8.55 (s, 1H), 8.18 (s, 1H), 7.88 (d,J = 8.8 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 4.00 (m, 1H), 3.43 (m, 2H),3.16 (s, 4H), 2.26 (d, J = 6.4 Hz, 1H), 1.29-0.63 (m, 6H). MS m/z (M⁺)333.9 9 (S)-2-Amino-3-phenyl-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propionamide ¹H NMR (300 MHz, CD₃OD) δ 7.90 (s, 1H), 8.05-7.47 (m, 2H),7.81 (d, J = 8.9 Hz, 1H), 7.34 (dt, J = 9.7, 7.8 Hz, 2H), 7.34 (dt, J =9.7, 7.8 IIz, 2II), 4.40 (dd, J = 8.1, 6.3 IIz, 1II), 3.46-3.30 (m,2II), 3.19 (dd, J = 14.0, 8.2 Hz, 1H). MS m/z (M⁺) 381.9 10(S)-2-Amino-3-benzyloxy-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propionamide: ¹H NMR (300 MHz, DMSO) δ 8.66 (s, 1H), 8.19 (s, 1H), 7.88(d, J = 8.9 Hz, 1H), 7.47 (d, J = 8.9 Hz, 1H), 7.35-7.18 (m, 5H), 4.56(q, J = 12.3 Hz, 2H), 4.44 (s, 1H), 4.11-3.77 (m, 2H). MS m/z (M⁺) 411.9(S)-2-amino-3-(4-fluorobenzyloxy)-N-(6-trifluoromethoxy-benzolhiazol-2-yl)-propanamide: ¹H NMR (300 MHz, DMSO) δ 8.19 (d, J =1.4 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.47 (ddd, J = 8.8, 2.5, 0.9 Hz,1H), 7.40-7.26 (m, 2H), 7.14-7.01 (m, 2H), 4.66-4.34 (m, 3H), 4.06-3.77(m, 2H).: MS m/z (M+) 429.9(S)-2-amino-3-(2,4-difluorobenzyloxy)-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propanamide: ¹H NMR (300 MHz, DMSO) δ 8.19 (d, J =1.3 Hz, 1H), 7.88 (d, J = 8.9 Hz, 1H), 7.62-7.36 (m, 2H), 7.23-7.12 (m,1H), 7.02 (ddd, J = 9.4, 8.0, 2.5 Hz, 1H), 4.59 (q, J = 12.3 Hz, 2H),4.44 (t, J = 4.3 Hz, 1H), 4.11-3.83 (m, 2H). MS m/z (M+) 447.9(S)-2-amino-3-methoxy-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propanamide: ¹H NMR (300 MHz, DMSO) δ 8.65 (bs, 2H), 8.18 (d, J = 1.5Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.46 (ddd, J = 8.8, 2.5, 0.9 Hz, 1H),4.42 (bs, 1H), 3.92 (dd, J = 10.8, 5.1 Hz, 1H), 3.82 (dd, J = 10.8, 3.8Hz, 1H), 3.31 (s, 3H). MS m/z (M+) 335.9(S)-N-(6-trifluoromethoxy-benzthiazol-2-yl)-pyrrolidine-2- carboxamide:¹H NMR (300 MHz, DMSO) δ 8.19-8.17 (m, 1H), 7.88 (d, J = 8.8 Hz, 1II),7.53-7.22 (m, 1II), 4.56 (dd, J = 8.5, 6.7 IIz, 1II), 3.41-3.13 (m, 2H),2.48-2.34 (m, 1H), 2.10-1.75 (m, 3H). MS m/z (M+) 331.9 (S)-tert-butyl3-(benzyloxy)-1-oxo-1-(6-trifluoromethoxy-benzothiazol-2-ylamino)-propan-2-ylcarbamate: ¹H NMR (300 MHz, CDCl₃) δ 7.78 (d, J =8.8 Hz, 1H), 7.69 (d, J = 1.2 Hz, 1H), 7.38-7.27 (m, 6H), 5.43 (d, J =7.3 IIz, 1II), 4.59 (q, J = 11.9 IIz, 2II), 4.05 (d, J = 9.7 IIz, 1II),3.69 (dd, J = 9.4, 5.6 Hz, 1H), 1.36 (s, 9H). MS m/z (M+) 512.0(S)-2-acetamido-3-(benzyloxy)-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propanamide: ¹H NMR (300 MHz, CDCl₃) δ 7.80 (d, J = 8.9 Hz, 1H),7.69 (s, 1H), 7.47-7.25 (m, 6H), 5.04 (t, J = 6.5 Hz, 1H), 4.63 (dd, J =33.0, 12.1 Hz, 2H), 4.39 (dd, J = 10.0, 6.3 Hz, 1H), 3.82 (dd, J = 9.8,7.1 Hz, 1H), 2.48 (s, 3H). MS m/z (M+) 453.9(S)-3-tert-butoxy-2-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide: ¹H NMR (300 MHz, CDCl₃) δ 7.77 (d, J = 9.2 Hz, 1H), 7.68(m, 1H), 7.30 (dm, J = 9.2 Hz, 1H), 3.62-3.78 (m, 3H), 1.21 (s, 9H). MSm/z (M⁺) 321.95

Example 2 (6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid methylester, Cpd 12.

6-Trifluoromethoxy-benzothiazol-2-ylamine (100 mg, 0.42 mmol),methylchloroformate (70 mg, 0.74 mmol), and triethylamine (64 mg, 0.64mmol) were combined in methylene chloride (3 mL) and strirred 24 h atambient temperature. The reaction was concentrated. The residue wastreated with methanol/water (1:1, 5 mL) and the solid collected byfiltration and dried under vacuum to afford(6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid methyl ester, Cpd12. ¹H NMR (300 MHz, DMSO) δ 8.22 (s, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.52(d, J=9.0 Hz, 1H), 3.97 (s, 1H), 3.44 (s, 3H).MS m/z (M⁺) 292.9

Following the procedure described above for Example 2 and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the compounds of the presentinvention in table 10 were prepared:

TABLE 10 Compound Compound Name and Characterization Data 13(6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid ethyl ester ¹H NMR(300 MHz, DMSO) δ 8.23 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.52 (d, J =8.7 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H). MS m/z(M⁺) 306.9 14 (6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acidpropyl ester ¹H NMR (300 MHz, DMSO) δ 12.15 (s, 1H), 8.10 (s, 1H), 7.77(d, J = 8.8 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 4.18 (t, J = 6.7 Hz, 2H),2.57-2.45 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). MS m/z (M⁺) 320.9 15(6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid butyl ester: ¹H NMR(300 MHz, DMSO) δ 12.14 (s, 1H), 8.09 (s, 1H), 7.77 (d, J = 8.8 Hz, 1H),7.39 (d, J = 7.4 Hz, 1H), 4.21 (t, J = 6.7 Hz, 1H), 1.73-1.31 (m, 2H),1.32 (t, J = 6.9 Hz, 2H), 0.88 (t, J = 6.7 Hz, 3H). MS m/z (M⁺) 334.9 16(6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid isobutyl ester: ¹HNMR (300 MHz, DMSO) δ 12.16 (s, 1H), 8.08 (s, 1H), 7.76 (d, J = 8.8 Hz,1H), 7.38 (d, J = 7.2 Hz, 1H), 3.97 (dd, J = 18.1, 6.6 Hz, 2H), 1.96(dt, J = 13.5, 6.8 Hz, 1H), 1.05 (d, J = 6.6 Hz, 3H). MS m/z (M⁺) 334.917 (6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid hexyl ester: ¹HNMR (300 MHz, DMSO) δ 8.12 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.42 (d, J= 7.4 Hz, 1H), 4.24 (t, J = 6.7 Hz, 2H), 1.67 (dd, J = 14.2, 6.8 Hz,2H), 1.35 (m, 6H), 0.91 (t, J = 6.7 Hz, 3H). MS m/z (M⁺) 362.9 18(6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid 2-dimethylamino-ethyl ester: ¹H NMR (300 MHz, CD₃OD) δ 7.85 (s, 1H), 7.75(d, J = 9.1 Hz, 1H), 7.42-7.27 (m, 1H), 4.86 (s, 6H), 4.64 (m, 2H), 3.58(m, 2H). MS m/z (M⁺) 349.8 19(6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid 3-dimethylamino-propyl ester: ¹H NMR (300 MHz, DMSO) δ 10.33 (s, 1H), 8.10(s, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 4.26 (dd, J= 18.9, 12.6 Hz, 2H), 3.16 (d, J = 15.6 Hz, 2H), 2.76 (d, J = 5.0 Hz,6H), 2.30-1.77 (m, 2H). MS m/z (M⁺) 363.9

Example 3 N-(6-Trifluoromethoxy-benzothiazol-2-yl)-succinamic acid, Cpd20.

6-Trifluoromethoxy-benzothiazol-2-ylamine (50 mg, 0.21 mmol), succinicanhydride (21 mg, 0.21 mmol), and triethylamine (42 mg, 0.42 mmol) werecombined in tetrahydrofuran and dimethylformamide (1 mL of each) andstrirred 24 h at ambient temperature. The reaction was purified usingreverse phase chromatography (10-90% acetonitrile:water both containing0.1% trifluoroacetic acid). The fractions containing product werecombined and lyophilized to affordN-(6-Trifluoromethoxy-benzothiazol-2-yl)-succinamic acid, Cpd 20. ¹H NMR(300 MHz, DMSO) δ 8.11 (s, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.41 (d, J=8.8Hz, 1H), 2.72 (d, J=6.8 Hz, 2H), 2.68-2.44 (m, 2H). MS m/z (M⁺) 334.8

Following the procedure described above for Example 1 and Example 3 andsubstituting the appropriate reagents, starting materials, andpurification methods known to those skilled in the art, the compounds ofthe present invention in table 11 were prepared:

TABLE 11 Compound Compound Name and Characterization Data 21N-(6-Trifluoromethoxy-benzothiazol-2-yl)-succinamic acid methyl ester¹HNMR (300 MHz, DMSO) δ 12.54 (s, 2H), 8.12 (s, 1H), 7.82 (d, J = 8.8 Hz,1H), 7.42 (d, J = 8.8 Hz, 1H), 3.60 (d, J = 9.2 Hz, 3H), 3.03-2.58 (m,2H), 1.76 (t, J = 6.6 Hz, 2H). MS m/z (M⁺) 348.9 22N-(6-Trifluoromethoxy-benzothiazol-2-yl)-succinamic acid tert-butylester: ¹H NMR (300 MHz, DMSO) δ 12.50 (s, 1H), 8.10 (s, 1H), 7.81 (d, J= 8.6 Hz, 1H), 7.40 (m, 1H), 3.59 (t, J = 6.6 Hz, 2H), 1.75 (t, J = 6.6Hz, 2H), 1.37 (s, 9H). MS m/z (MH⁺-C₄H₉) 334.8 23N-Pyridin-3-ylmethyl-N′-(6-trifluoromethoxy-benzothiazol-2-yl)-succinamide: ¹H NMR (300 MHz, DMSO) δ 12.50 (s, 1H), 8.84-8.42 (m, 2H),8.10 (d, J = 7.4 Hz, 2H), 7.81 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 7.9 Hz,1H), 7.35 (dd, J = 36.7, 27.4 Hz, 1H), 4.40 (d, J = 5.8 Hz, 2H), 2.78(t, J = 6.7 Hz, 2H), 2.57 (t, J = 6.7 Hz, 2H). MS m/z (M⁺) 424.9 24N-(2-Morpholin-4-yl-ethyl)-N′-(6-trifluoromethoxy-benzothiazol-2-yl)-succinamide: ¹H NMR (300 MHz, DMSO) δ 12.51 (s, 1H), 9.61 (s, 1H),8.23 (s, 1H), 8.11 (s, 1H), 7.82 (d, J = 8.9 Hz, 1H), 7.42 (d, J = 8.9Hz, 1H), 3.96 (s, 2H), 3.64 (s, 3H), 3.44 (m, 6H), 3.18 (m, 3H), 2.76(d, J = 6.4 Hz, 2H), 2.53 (dd, J = 15.1, 4.8 Hz, 1H). MS m/z (M⁺) 446.9

Following the procedure described above for Example 1 and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the compounds of the presentinvention in table 12 were prepared:

TABLE 12 Compound Compound Name and Characterization Data 255-Methylamino-pentanoic acid (6-trifluoromethoxy-benzothiazol-2-yl)-amide: ¹H NMR (300 MHz, CD₃OD) δ 7.8 (m, 1H), 7.38 (d, J = 8.9 Hz,1H), 3.76 (t, J = 6.6 Hz, 2H), 3.18 (m, 2H), 2.63 (t, J = 7.0 Hz, 2H),2.11 (m, 2H), 1.83 (m, 2H). MS m/z (M⁺) 333.9 26 5-Amino-pentanoic acid(6-trifluoromethoxy-benzothiazol-2-yl)- amide ¹H NMR (300 MHz, CD₃OD) δ8.00-7.65 (m, 2H), 7.34 (d, J = 8.9 Hz, 1H), 3.72 (t, J = 6.6 Hz, 2H),3.20-2.89 (m, 2H), 2.71 (t, J = 7.0 Hz, 2H), 2.17-1.93 (m, 2H),1.93-1.73 (m, 2H). MS m/z (M + Na⁺) 342.0 272-(2-Nitro-phenyl)-N-(6-trifluoromethoxy-benzothiazol-2-yl)- acetamide¹H NMR (300 MHz, DMSO) δ 12.79 (s, 1H), 8.12 (d, J = 8.2 Hz, 2H), 7.84(d, J = 8.8 Hz, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.62 (d, J = 5.6 Hz, 2H),7.42 (d, J = 8.7 Hz, 1H), 4.30 (s, 2H). MS m/z (M⁺) 397.9 284-Amino-N-(6-trifluoromethoxy-benzothiazol-2-yl)-benzamide ¹H NMR (300MHz, DMSO) δ 8.10 (s, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.81 (d, J = 8.8Hz, 1H), 7.66 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 6.69 (s, 2H). MS m/z(M⁺) 353.9 292-(1-Aminomethyl-cyclohexyl)-N-(6-trifluoromethoxy-benzothiazol-2-yl)-acetamide: ¹H NMR (300 MHz, DMSO) δ 12.70 (s, 1H), 8.88 (s, 1H),8.14 (s, 1H), 7.97 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8Hz, 1H), 3.01 (d, J = 5.6 Hz, 4H), 2.90 (s, 3H), 2.80 (s, 3H), 2.74 (s,3H), 1.47 (d, J = 8.8 Hz, 3H). MS m/z. (MH⁺) 388.0

Example 4

Synthesis of(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamideTo a mixture of Riluzole (0.6 gm, 2.4 mmol), (S)-Boc proline (0.77 gm,3.6 mmol) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) (0.7gm, 3.6 mmol), diisopropylethylamine (0.47 gm, 3.6 mmol) and4-Dimethylaminopyridine (0.06 gm, 0.5 mmol) in anhydrousN,N-dimethylformamide (8 mL) and stirred for 20 hours. The reactionmixture was quenched with water (5 mL) diluted with ethyl acetate (50mL) and the aqueous layer was extracted with ethyl acetate (2×5 mL). Thecombined organic layers were washed with 1N HCl (10 mL), saturatedNaHCO₃ (10 mL), water (2×20 mL) and brine (10 mL). The organic layer wasthen filtered through Na₂SO₄ concentrated under reduced pressure andpurified via flash column chromatography using 20-30% ethyl acetate thatafforded a white solid. This was dissolved in 1:1 4N HCl in 1,4-dioxane:1,4-dioxane and stirred for 3 hours. After 3 hours the solvent wasremoved under reduced pressure and the resulting solid was washed withethyl acetate (5 mL) and ether (5 mL). The solid was then filtered anddried to afford(S)—N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide(60%). ¹H NMR (300 MHz, DMSO) δ 8.19-8.17 (m, 1H), 7.88 (d, J=8.8 Hz,1H), 7.53-7.22 (m, 1H), 4.56 (dd, J=8.5, 6.7 Hz, 1H), 3.41-3.13 (m, 2H),2.48-2.34 (m, 1H), 2.10-1.75 (m, 3H). MS m/z (M+) 331.9.

Synthesis oftert-butyl-N—[(S)-2-(benzyloxy)-1-{[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}ethyl]carbamate.To a solution of 6-(trifluoromethoxy)-1,3-benzothiazol-2-amine(Riluzole, 5.0 g, 21 mmol), (S)—N-t-butyloxycarbonyl-serine-O-benzylether (7.6 g, 26 mmol), hydroxybenzotriazole (4.0 g, 26 mmol),4-dimethylaminopyridine (0.32 g, 2.6 mmol) and diisopropylethylamine(3.4 g, 26 mmol, 4.7 mL) in N,N-dimethylformamide (100 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) (5.0 g, 26 mmol) and themixture stiffed for 24 hours. The reaction mixture was diluted withethyl acetate (500 mL) and washed with water (2×300 mL), 1N HCl (6×200mL), water (300 mL), 1M sodium carbonate (200 mL), brine (100 mL), dried(Na₂SO₄) and evaporated to a colorless viscous oil (5.0 g, 47%). ¹H-NMR(300 MHz, CDCl₃) δ 7.77 (d, J=9.1 Hz, 1H), 7.69 (d, J=1.1 Hz, 1H), 7.30(m, 6H), 5.45 (d, J=7.3 Hz, 1H), 4.61 (d ABq, J=12.0 Hz, 1H), 4.56 (dABq, J=12.0 Hz, 1H), 4.03 (m, 1H), 3.69 (dd, J=9.6 Hz, J=5.5 Hz, 1H),1.47 (s, 9H); ESI MS (M+H)⁺=512.

Synthesis of(S)-2-amino-3-(benzyloxy)-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]propanamide.A solution of tert-butylN-RS)-2-(benzyloxy)-1-{[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}ethyl]carbamate(5.0 g, 9.8 mmol) in dichloromethane (30 mL) and trifluoroacetic acid(15 mL) was stirred for 1 hour then evaporated to dryness. The residuewas dissolved in ethyl acetate (100 mL) and washed with saturated sodiumbicarbonate solution (100 mL), water (100 mL) and brine (50 mL). Themixture was dried (Na₂SO₄) and evaporated to a gum that was dissolved inacetonitrile (150 mL) and treated with concentrated HCl (1.2 mL). Thehydrochloride salt precipitated and was filtered, washed with ethylacetate and dried to leave 3.0 g (68%) of off-white powder. ¹H-NMR (300MHz, DMSO-d₆) δ 8.16 (dd, J=1.5 Hz, J=1.0 Hz, 1H), 7.86 (d, J=8.8 Hz,1H), 7.45 (ddd, J=8.8 Hz, J=1.0 Hz, J=1.5 Hz, 1H), 7.25 (m, 5H), 4.54(ABq, J=12.3 Hz, 2H), 4.41 (dd, J=4.1 Hz, J=4.4 Hz, 1H), 3.93 (m, 2H);ESI MS (M+H)⁺=412.

Formulations

The present invention also relates to compositions or formulations whichcomprise the riluzole prodrug agents according to the present invention.In general, the compositions of the present invention comprise aneffective amount of one or more riluzole prodrug agents and saltsthereof according to the present invention which are effective and oneor more excipients.

For the purposes of the present invention the term “excipient” and“carrier” are used interchangeably throughout the description of thepresent invention and said terms are defined herein as, “ingredientswhich are used in the practice of formulating a safe and effectivepharmaceutical composition.”

The formulator will understand that excipients are used primarily toserve in delivering a safe, stable, and functional pharmaceutical,serving not only as part of the overall vehicle for delivery but also asa means for achieving effective absorption by the recipient of theactive ingredient. An excipient may fill a role as simple and direct asbeing an inert filler, or an excipient as used herein may be part of apH stabilizing system or coating to insure delivery of the ingredientssafely to the stomach. The formulator can also take advantage of thefact the compounds of the present invention have improved cellularpotency, pharmacokinetic properties, as well as improved oralbioavailability.

The present teachings also provide pharmaceutical compositions thatinclude at least one compound described herein and one or morepharmaceutically acceptable carriers, excipients, or diluents. Examplesof such carriers are well known to those skilled in the art and can beprepared in accordance with acceptable pharmaceutical procedures, suchas, for example, those described in Remington's Pharmaceutical Sciences,17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton,Pa. (1985), the entire disclosure of which is incorporated by referenceherein for all purposes. As used herein, “pharmaceutically acceptable”refers to a substance that is acceptable for use in pharmaceuticalapplications from a toxicological perspective and does not adverselyinteract with the active ingredient. Accordingly, pharmaceuticallyacceptable carriers are those that are compatible with the otheringredients in the formulation and are biologically acceptable.Supplementary active ingredients can also be incorporated into thepharmaceutical compositions.

Compounds of the present teachings can be administered orally orparenterally, neat or in combination with conventional pharmaceuticalcarriers. Applicable solid carriers can include one or more substanceswhich can also act as flavoring agents, lubricants, solubilizers,suspending agents, fillers, glidants, compression aids, binders ortablet-disintegrating agents, or encapsulating materials. The compoundscan be formulated in conventional manner, for example, in a mannersimilar to that used for known riluzole prodrug agents. Oralformulations containing a compound disclosed herein can comprise anyconventionally used oral form, including tablets, capsules, buccalforms, troches, lozenges and oral liquids, suspensions or solutions. Inpowders, the carrier can be a finely divided solid, which is anadmixture with a finely divided compound. In tablets, a compounddisclosed herein can be mixed with a carrier having the necessarycompression properties in suitable proportions and compacted in theshape and size desired. The powders and tablets can contain up to 99% ofthe compound.

Capsules can contain mixtures of one or more compound(s) disclosedherein with inert filler(s) and/or diluent(s) such as pharmaceuticallyacceptable starches (e.g., corn, potato or tapioca starch), sugars,artificial sweetening agents, powdered celluloses (e.g., crystalline andmicrocrystalline celluloses), flours, gelatins, gums, and the like.

Useful tablet formulations can be made by conventional compression, wetgranulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants, surfacemodifying agents (including surfactants), suspending or stabilizingagents, including, but not limited to, magnesium stearate, stearic acid,sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin,cellulose, methyl cellulose, microcrystalline cellulose, sodiumcarboxymethyl cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodiumcitrate, complex silicates, calcium carbonate, glycine, sucrose,sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin,mannitol, sodium chloride, low melting waxes, and ion exchange resins.Surface modifying agents include nonionic and anionic surface modifyingagents. Representative examples of surface modifying agents include, butare not limited to, poloxamer 188, benzalkonium chloride, calciumstearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitanesters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate,magnesium aluminum silicate, and triethanolamine Oral formulationsherein can utilize standard delay or time-release formulations to alterthe absorption of the compound(s). The oral formulation can also consistof administering a compound disclosed herein in water or fruit juice,containing appropriate solubilizers or emulsifiers as needed.

Liquid carriers can be used in preparing solutions, suspensions,emulsions, syrups, elixirs, and for inhaled delivery. A compound of thepresent teachings can be dissolved or suspended in a pharmaceuticallyacceptable liquid carrier such as water, an organic solvent, or amixture of both, or a pharmaceutically acceptable oils or fats. Theliquid carrier can contain other suitable pharmaceutical additives suchas solubilizers, emulsifiers, buffers, preservatives, sweeteners,flavoring agents, suspending agents, thickening agents, colors,viscosity regulators, stabilizers, and osmo-regulators. Examples ofliquid carriers for oral and parenteral administration include, but arenot limited to, water (particularly containing additives as describedherein, e.g., cellulose derivatives such as a sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols andpolyhydric alcohols, e.g., glycols) and their derivatives, and oils(e.g., fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can be an oily ester such as ethyl oleateand isopropyl myristate. Sterile liquid carriers are used in sterileliquid form compositions for parenteral administration. The liquidcarrier for pressurized compositions can be halogenated hydrocarbon orother pharmaceutically acceptable propellants.

Liquid pharmaceutical compositions, which are sterile solutions orsuspensions, can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Compositions for oral administration can bein either liquid or solid form.

Preferably the pharmaceutical composition is in unit dosage form, forexample, as tablets, capsules, powders, solutions, suspensions,emulsions, granules, or suppositories. In such form, the pharmaceuticalcomposition can be sub-divided in unit dose(s) containing appropriatequantities of the compound. The unit dosage forms can be packagedcompositions, for example, packeted powders, vials, ampoules, prefilledsyringes or sachets containing liquids. Alternatively, the unit dosageform can be a capsule or tablet itself, or it can be the appropriatenumber of any such compositions in package form. Such unit dosage formcan contain from about 1 mg/kg of compound to about 500 mg/kg ofcompound, and can be given in a single dose or in two or more doses.Such doses can be administered in any manner useful in directing thecompound(s) to the recipient's bloodstream, including orally, viaimplants, parenterally (including intravenous, intraperitoneal andsubcutaneous injections), rectally, vaginally, and transdermally.

When administered for the treatment or inhibition of a particulardisease state or disorder, it is understood that an effective dosage canvary depending upon the particular compound utilized, the mode ofadministration, and severity of the condition being treated, as well asthe various physical factors related to the individual being treated. Intherapeutic applications, a compound of the present teachings can beprovided to a patient already suffering from a disease in an amountsufficient to cure or at least partially ameliorate the symptoms of thedisease and its complications. The dosage to be used in the treatment ofa specific individual typically must be subjectively determined by theattending physician. The variables involved include the specificcondition and its state as well as the size, age and response pattern ofthe patient.

In some cases it may be desirable to administer a compound directly tothe airways of the patient, using devices such as, but not limited to,metered dose inhalers, breath-operated inhalers, multi dose dry-powderinhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosoldispensers, and aerosol nebulizers. For administration by intranasal orintrabronchial inhalation, the compounds of the present teachings can beformulated into a liquid composition, a solid composition, or an aerosolcomposition. The liquid composition can include, by way of illustration,one or more compounds of the present teachings dissolved, partiallydissolved, or suspended in one or more pharmaceutically acceptablesolvents and can be administered by, for example, a pump or asqueeze-actuated nebulized spray dispenser. The solvents can be, forexample, isotonic saline or bacteriostatic water. The solid compositioncan be, by way of illustration, a powder preparation including one ormore compounds of the present teachings intermixed with lactose or otherinert powders that are acceptable for intrabronchial use, and can beadministered by, for example, an aerosol dispenser or a device thatbreaks or punctures a capsule encasing the solid composition anddelivers the solid composition for inhalation. The aerosol compositioncan include, by way of illustration, one or more compounds of thepresent teachings, propellants, surfactants, and co-solvents, and can beadministered by, for example, a metered device. The propellants can be achlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or otherpropellants that are physiologically and environmentally acceptable.

Compounds described herein can be administered parenterally orintraperitoneally. Solutions or suspensions of these compounds or apharmaceutically acceptable salts, hydrates, or esters thereof can beprepared in water suitably mixed with a surfactant such ashydroxyl-propylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, and mixtures thereof in oils. Underordinary conditions of storage and use, these preparations typicallycontain a preservative to inhibit the growth of microorganisms.

The pharmaceutical forms suitable for injection can include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In some embodiments, the form can sterile and its viscositypermits it to flow through a syringe. The form preferably is stableunder the conditions of manufacture and storage and can be preservedagainst the contaminating action of microorganisms such as bacteria andfungi. The carrier can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (e.g., glycerol, propylene glycol andliquid polyethylene glycol), suitable mixtures thereof, and vegetableoils.

Compounds described herein can be administered transdermally, i.e.,administered across the surface of the body and the inner linings ofbodily passages including epithelial and mucosal tissues. Suchadministration can be carried out using the compounds of the presentteachings including pharmaceutically acceptable salts, hydrates, oresters thereof, in lotions, creams, foams, patches, suspensions,solutions, and suppositories (rectal and vaginal).

Transdermal administration can be accomplished through the use of atransdermal patch containing a compound, such as a compound disclosedherein, and a carrier that can be inert to the compound, can benon-toxic to the skin, and can allow delivery of the compound forsystemic absorption into the blood stream via the skin. The carrier cantake any number of forms such as creams and ointments, pastes, gels, andocclusive devices. The creams and ointments can be viscous liquid orsemisolid emulsions of either the oil-in-water or water-in-oil type.Pastes comprised of absorptive powders dispersed in petroleum orhydrophilic petroleum containing the compound can also be suitable. Avariety of occlusive devices can be used to release the compound intothe blood stream, such as a semi-permeable membrane covering a reservoircontaining the compound with or without a carrier, or a matrixcontaining the compound. Other occlusive devices are known in theliterature.

Compounds described herein can be administered rectally or vaginally inthe form of a conventional suppository. Suppository formulations can bemade from traditional materials, including cocoa butter, with or withoutthe addition of waxes to alter the suppository's melting point, andglycerin. Water-soluble suppository bases, such as polyethylene glycolsof various molecular weights, can also be used.

Lipid formulations or nanocapsules can be used to introduce compounds ofthe present teachings into host cells either in vitro or in vivo. Lipidformulations and nanocapsules can be prepared by methods known in theart.

To increase the effectiveness of compounds of the present teachings, itcan be desirable to combine a compound with other agents effective inthe treatment of the target disease. For example, other active compounds(i.e., other active ingredients or agents) effective in treating thetarget disease can be administered with compounds of the presentteachings. The other agents can be administered at the same time or atdifferent times than the compounds disclosed herein.

Compounds of the present teachings can be useful for the treatment orinhibition of a pathological condition or disorder in a mammal, forexample, a human subject. The present teachings accordingly providemethods of treating or inhibiting a pathological condition or disorderby providing to a mammal a compound of the present teachings incldingits pharmaceutically acceptable salt) or a pharmaceutical compositionthat includes one or more compounds of the present teachings incombination or association with pharmaceutically acceptable carriers.Compounds of the present teachings can be administered alone or incombination with other therapeutically effective compounds or therapiesfor the treatment or inhibition of the pathological condition ordisorder.

Non-limiting examples of compositions according to the present inventioninclude from about 0.001 mg to about 1000 mg of one or more riluzoleprodrug according to the present invention and one or more excipients;from about 0.01 mg to about 100 mg of one or more riluzole prodrugaccording to the present invention and one or more excipients; and fromabout 0.1 mg to about 10 mg of one or more riluzole prodrug according tothe present invention; and one or more excipients.

Procedures

The following procedures can be utilized in evaluating and selectingcompounds as riluzole prodrugs.

Stability in Simulated Gastric Fluid (SGF) and Simulated IntestinalFluid (SIF). Procedure from Baudy et. al. (J. Med. Chem. 2009, 52,771-778) used. The physiological stability of prodrugs was determined byexamining the stability of the compound in SGF, and SIF at 37° C. Thecompounds were prepared in a 9:1 mixture of the appropriate testcomponent (SGF, SIF) and acetonitrile to a final concentration of 0.01mg/mL. The samples were thoroughly mixed and maintained at 37° C. Eachsample was injected consecutively onto an Agilent 1100 system (Luna C18,3 μm, 50 mm×3 mm; 1 mL/min; mobile phase of 0.1% trifluoroacetic acid inwater/0.1% trifluoroacetic acid in acetonitrile) after a 3 h period. Thepercent remaining of prodrug was calculated by comparing the area ofprodrug compound versus riluzole generated. The identities of the parentcompounds and conversion products were confirmed by LC/MS.

Plasma Stability: Assessment of plasma stability was carried out byindividual incubations of drug candidates in fresh mouse or humancontrol plasma at a concentration of 1 uM for 1 hour at 37° C. Afterwhich, the samples were de-proteinized by addition of 2 volumes ofacetonitrile containing 0.1% formic acid and internal standard, vortexmixed for 2 minutes and centrifuged at 4000 rpm for 10 minutes to pelletprecipitated protein. The resulting supernatant containing the drugcandidates was diluted 5-fold with water containing 0.1% formic acid andsubmitted to LC-MS/MS analysis. All determinations were done intriplicate. Plasma stability was expressed as percent of controlremaining.

Metabolic Stability: In vitro metabolic stability was determined inpooled mouse or human liver microsomes (BD Gentest) at a proteinconcentration of 0.5 mg/mL in reaction buffer (100 mM KH₂PO₄, pH 7.4 and12 mM MgCl₂). Each drug candidate was added to a final concentration of1 uM. This mixture was pre-warmed to 37° C. for 10 minutes prior tostarting the reaction with the addition of β-Nicotinamide adeninedinucleotide 2′-phosphate reduced (NADPH) to a final concentration of 1mM. A parallel incubation lacking NADPH served as the control. Afterincubation for 30 min at 37° C., the reactions were quenched by theaddition of acetonitrile containing 0.1% formic acid and internalstandard, vortex mixed for 2 minutes and centrifuged at 4000 rpm for 10minutes to pellet the precipitated protein. The resulting supernatantcontaining the drug candidate and its potential metabolites was diluted5-fold with water containing 0.1% formic acid and submitted to LC-MS/MSanalysis. Metabolic stability was expressed as percent of controlremaining

LC-MS/MS Analysis: An aliquot from each incubation was analyzed byLC-MS/MS with SRM detection in the positive ionization mode using anABSciex API 5500 QTrap Mass Spectrometer interfaced via the ABSciexTurbo V IonSpray source (ESI) to an Eksigent ExpressHT LC system. Bestpeak shape and separation from interfering matrix species was affordedby an Eksigent 3C18-CL-300, 3μ, 50×1 mm column. A fast gradient, from 15to 85% organic in 2.5 minutes, with run time of 5.0 minutes, and flowrate of 50 uL/min was utilized. Peak areas were integrated usingMultiQuant v2.0 software from ABSciex.

TABLE 13 Values represent percent of prodrug metabolized to riluzole.Plasma Metabolic Metabolic Plasma Stability SGF SIF Stability mouseStability human Stability mouse Human (1 Cpd # (3 hours) (3 hours) (30minutes) (30 minutes) (1 hour) hour) 1 4 7 11 3 2 0 50 10 4 36 15 4 3 012 18 47 6 5 24 0 25 3 7 0 50 1 0 28 10 9 2 0 0 7 10 0 0 0 15 52 9 11 040 40 6 45 11 12 0 0 10 0 0 15 13 0 0 8 7 0 0 14 0 0 15 34 0 0 15 0 0 5313 9 0 16 5 0 23 14 0 0 17 0 18 0 0 13 10 3 0 19 0 0 71 0 0 0 20 0 0 700 0 16 21 3 0 77 34 99 25 22 0 0 0 21 0 0 23 0 10 0 4 26 0 24 0 60 25 00 78 0 0 0 26 0 0 66 19 0 5 27 0 0 59 22 0 13 28 0 0 24 80 0 0 29 0 50

1. A compound having formula (I):

including hydrates, solvates, pharmaceutically acceptable salts, andcomplexes thereof, wherein: R¹ is selected from the group consisting ofOR², CR^(3a)R^(3b)NH₂, CR^(3a)R^(3b)NR^(7a)R^(7b), CH₂CH₂CO₂R⁴,CH₂CH₂CONHR⁵, (CR^(6a)R^(6b))_(m)NR^(7a)R^(7b), CH₂Ar, and optionallysubstituted phenyl ring; R² is selected from the group consisting ofoptionally substituted C1-C6 alkyl and CH₂(CH₂)_(n)NR^(8a)R^(8b); n=1 or2; R^(3a) and R^(3b) are each independently selected from the groupconsisting of hydrogen, optionally substituted C1-C6 alkyl, optionallysubstituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl,CH₂R^(4a), optionally substituted phenyl, optionally substituted benzyl,optionally substituted CH₂CH₂Ar, optionally substituted CH₂heteroaryl,CH₂OR⁹, CH(CH₃)OR⁹, CH₂SR⁹, CH₂CH₂,SCH₃, CH₂CH₂SO₂CH₃,CH₂CH₂CH₂NR^(10a)R^(10b); CH₂COR^(9a), and CH₂CH₂COR^(9a); R^(3a) andR^(3b) are taken together with an atom to which they are bound to forman optionally substituted three to six membered saturated heterocyclicring comprising two to five carbon atoms and a member selected from thegroup consisting of O, NR^(7a), S, and SO₂; R⁴ is selected from thegroup consisting of hydrogen and optionally substituted C1-C6 Alkyl;R^(4a) is selected from the group consisting of hydrogen, optionallysubstituted C1-C6 Alkyl, optionally substituted C3-C6 cycloalkyl, andoptionally substituted four to six membered saturated heterocyclic ringcomprising three to five carbon atoms and a member selected from thegroup consisting of O, NR^(7a), S, and SO₂; R⁵ is selected from thegroup consisting of hydrogen, optionally substituted C1-C6 Alkyl,CH₂CH₂NR^(10a)R^(10b)), and CH₂R¹¹; R^(6a) and R^(6b) are, at eachoccurrence, independently selected from the group consisting of hydrogenand optionally substituted C1-C6 alkyl; R^(6a) and R^(6b) are takentogether with the atom to which they are bound to form an optionallysubstituted 6 membered ring; m=3 or 4; m=1 or 2; R^(7a) and R^(7b) areeach independently selected from the group consisting of hydrogen,methyl, COR¹², and CO2R¹²; R^(3a) and R^(7a) are taken together with theatoms to which they are bound to form an optionally substituted three tosix membered ring consisting of all carbons and one nitrogen atom;R^(3a) and R⁷a are taken together with the atoms to which they are boundto form an optionally substituted 1,2,3,4-tetrahydro-isoquinoline ringsystem; R^(3a) and R^(7a) are taken together with the atoms to whichthey are bound to form an optionally substituted2,3-Dihydro-1H-isoindole ring system; R^(3a) and R^(7a) are takentogether with the atoms to which they are bound to form a optionallysubstituted six membered saturated heterocyclic ring comprising fourcarbons, one nitrogen atom, and a member selected from the groupconsisting of O, NR^(7a), S, and SO₂; R^(6a) and R^(7a) are takentogether with the atoms to which they are bound to form an optionallysubstituted three to six membered ring comprising all carbons and onenitrogen atom; R^(6a) and R^(7a) are taken together with the atoms towhich they are bound to form an optionally substituted1,2,3,4-tetrahydro-isoquinoline ring system; R^(6a) and R^(7a) are takentogether with the atoms to which they are bound to form an optionallysubstituted 2,3-Dihydro-1H-isoindole ring system; R^(6a) and R^(7a) aretaken together with the atoms to which they are bound to form aoptionally substituted six membered saturated heterocyclic ringconsisting of four carbons, one nitrogen atom, and a member selectedfrom the group consisting of O, NR^(7a), S, and SO₂; R^(8a) and R^(8b)are each independently optionally substituted C1-C6 alkyl; R⁹ isselected from the group consisting of hydrogen, C1-C6 alkyl, optionallysubstituted phenyl, optionally substituted benzyl, and optionallysubstituted CH₂CH₂Ar; R^(9a) is selected from the group consisting ofOH, C1-C6 alkoxy, and NH₂; R^(10a) and R^(10b) are each independently isselected from the group consisting of hydrogen and optionallysubstituted C1-C6 alkyl; R^(10a) and R^(10B) and are taken together withthe atom to which they are bound to form an optionally substituted ringhaving 5 to 6 ring atoms; R^(10a) and R^(10B) and are taken togetherwith the atom to which they are bound to form an optionally substitutedring having 5 to 6 ring atoms containing an oxygen; R^(10a) and R^(10B)and are taken together with the atom to which they are bound to form anoptionally substituted ring having 5 to 6 ring atoms containing twonitrogen atoms; R¹¹ is selected from the group consisting of optionallysubstituted phenyl and optionally substituted heteroaryl; R¹² is C1-C6alkyl; Ar is selected from the group consisting of optionallysubstituted phenyl and optionally substituted naphthyl ring; Ar isoptionally substituted with 0-5 moieties selected from the groupconsisting of deuterium, halogen, trifluoromethyl, triflouromethoxy,cyano, NR^(7a)R^(7b), CONR^(8a)R^(8b), C1-C6 alkyl, and C1-C6 alkoxy.2-29. (canceled)